CENTRAL NERVOUS SYSTEM DEPRESSANTS. ANTICONVULSANTS
(ANTIEPILEPTIC DRUGS). ANTIPARKINSON DRUGS
General CNS depressants: neuroleptics, tranquilizers,
sedatives. Lithium preparations
Central nervous system depressants slow down the operation of the brain.
They first affect those areas of the brain that control a person’s conscious,
voluntary actions. As dosage increases, depressants begin to affect the parts
of the brain controlling the body’s automatic, unconscious processes, such as
heartbeat and respiration.
Alcohol is the most familiar, and most widely
abused depressant. With some exceptions, all depressants affect people in much
the same way as does alcohol.
Most depressant users ingest these drugs orally. However, a few abusers
will inject their drugs intravenously. The injection paraphernalia used by
barbiturate abusers are similar to those used by heroin addicts, although a
wider gauge hypodermic needle is used, because the barbiturate solution is
thicker than the heroin solution. The injection sites on the skin of a
barbiturate abuser exhibit large swellings, and may develop ulceration’s
resembling cigarette burns.
The affects of depressants are once again compared to those of alcohol -
reduced social inhibitions, impaired ability to divide attention, slow
reflexes, impaired judgment and concentration, impaired vision and
coordination, slurred, mumbled or incoherent speech, a wide variety of
emotional effects, such as euphoria, depression, suicidal tendencies, laughing
or crying for no apparent reason, etc.
Depressants vary in the amount of time it takes the user to feel the
effects and also the amount of time the effects are felt. Some depressants act
very quickly, and begin to affect their user within seconds. Others act more
slowly, sometimes taking one-half hour or more to begin to exert an influence.
The quick-acting depressants also tend to be relatively short acting: in some
cases their effects wear off in a matter of minutes. The slow-acting
depressants, on the other hand, tend to produce longer-acting effects.
Overdoses of depressants produce effects that are the same as alcohol
overdoses. The person becomes extremely drowsy and passes out. Their heartbeat
slows and respiration will become shallow. Their skin may feel cold and clammy,
and death may result from respiratory failure
General CNS depressants: neuroleptics, tranquilizers,
sedatives. Lithium preparations
Central
nervous system depressants slow down the operation of the brain. They first
affect those areas of the brain that control a person’s conscious, voluntary
actions. As dosage increases, depressants begin to affect the parts of the
brain controlling the body’s automatic, unconscious processes, such as
heartbeat and respiration.
Alcohol is
the most familiar and most widely abused depressant. With some exceptions, all
depressants affect people in much the same way as do alcohol.
Most
depressant users ingest these drugs orally. However, a few abusers will inject
their drugs intravenously. The injection paraphernalia used by barbiturate
abusers are similar to those used by heroin addicts, although a wider gauge
hypodermic needle is used, because the barbiturate solution is thicker than the
heroin solution. The injection sites on the skin of a barbiturate abuser
exhibit large swellings, and may develop ulceration’s resembling cigarette
burns.
The affects
of depressants are once again compared to those of alcohol - reduced social
inhibitions, impaired ability to divide attention, slow reflexes, impaired
judgment and concentration, impaired vision and coordination, slurred, mumbled
or incoherent speech, a wide variety of emotional effects, such as euphoria,
depression, suicidal tendencies, laughing or crying for no apparent reason,
etc.
Depressants
vary in the amount of time it takes the user to feel the effects and also the
amount of time the effects are felt. Some depressants act very quickly, and
begin to affect their user within seconds. Others act more slowly, sometimes
taking one-half hour or more to begin to exert an influence. The quick-acting
depressants also tend to be relatively short acting: in some cases their
effects wear off in a matter of minutes. The slow-acting depressants, on the
other hand, tend to produce longer-acting effects.
Overdoses
of depressants produce effects that are the same as alcohol overdoses. The
person becomes extremely drowsy and passes out. Their heartbeat slows and
respiration will become shallow. Their skin may feel cold and clammy, and death
may result from respiratory failure.
Neuroleptic:
synonym for antipsychotic drug; originally indicated drug with antipsychotic
efficacy but with neurologic (extrapyramidal motor) side effects
Typical neuroleptic: older agents fitting this description
Atypical neuroleptic: newer agents: antipsychotic efficacy with reduced or
no neurologic side effects
The neuroleptic
drugs (also called antipsychotic drugs, or major
tranquilizers) are used primarily to treat
schizophrenia, but they are also effective in other psychotic states, such as
manic states with psychotic symptoms such as grandiosity or paranoia and
hallucinations, and delirium. All currently available
antipsychotic drugs that alleviate symptoms of schizophrenia decrease
dopaminergic and/or serotonergic neurotransmission. The traditional or
“typical” neuroleptic drugs (also called conventional or first-generation
antipsychotics) are competitive inhibitors at a variety of receptors, but their
antipsychotic effects reflect competitive blocking of dopamine receptors. These
drugs vary in potency. For example, chlorpromazine is a low-potency drug, and
fluphenazine is a high-potency agent. No one drug is clinically more effective
than another. In contrast, the newer antipsychotic drugs are referred to as “atypical”
(or second-generation antipsychotics), because they have fewer extrapyramidal
adverse effects than the older, traditional agents. These drugs appear to owe
their unique activity to blockade of both serotonin and dopamine (and, perhaps,
other) receptors. Current antipsychotic therapy commonly employs the use of the
atypical agents to minimize the risk of debilitating movement disorders
associated with the typical drugs that act primarily at the D2 dopamine recep tor. All of the atypical antipsychotics exhibit an efficacy that is
equivalent to, or occasionally exceeds, that of the typical neuroleptic agents.
However, consistent differences in therapeutic efficacy among the individual
atypical neuroleptics have not been established, and individual patient
response and comorbid conditions must often be used as a guide in drug
selection. Neuroleptic drugs are not curative and do not eliminate the
fundamental and chronic thought disorder, but they often decrease the intensity
of hallucinations and delusions and permit the person with schizophrenia to
function in a supportive environment.
Dopamine-blocking actions of neuroleptic drugs.
TYPICAL
NEUROLEPTICS:
PHENOTHIAZINES:
Chlorpromazine
(Thorazine ® )
Thioridazine
(Mellaril ® )
Fluphenazine
(Prolixin ® )
THIOXANTHENE
Thiothixene
(Navane® )
OTHER
ATYPICAL
NEUROLEPTICS:
Risperidone
(Risperdal ® ; most frequently prescribed in U.S.)
Clozapine
(Clozaril ® )
Olanzapine
(Zyprexa ® )
Quetiapine
(Seroquel ® ) Haloperidol (Haldol ® )
The older,
typical neuroleptics are effective antipsychotic agents with neurologic side
effects involving the extrapyramidal motor system.
Typical
neuroleptics block the dopamine-2 receptor.
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention,
impotence
Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension with reflex tachycardia, sedation
Antihistamine effect: sedation,
weight gain
EXTRAPYRAMIDAL MOTOR
SIDE EFFECTS (EPS).
Dystonia
Neuroleptic malignant syndrome
Parkinsonism
Tardive dyskinesia
Akathisia
Other side effects
Increased prolactin secretion
(common with all; from dopamine blockade)
Weight gain (common,
antihistamine effect?)
Photosensitivity (common with
phenothiazines)
Lowered seizure threshold
(common with all)
Leucopenia, agranulocytosis
(rare; with phenothiazines)
Retinal pigmentopathy (rare;
with phenothiazines)
Chlorpromazine and
thioridazine produce marked autonomic side
effects and sedation; EPS tend to be weak (thioridazine) or moderate
(chlorpromazine).
Haloperidol, thiothixene and
fluphenazine produce weak autonomic and
sedative effects, but EPS are marked.
Blockade of alpha-1 adrenergic
receptors
Blockade of muscarinic cholinergic
receptors
Blockade of histamine-1
receptors
Clozapine is a prototype 'broad-spectrum' antagonist. Its binding profile is quite
different from other anti-psychotics both within and outside the dopaminergic
system. It has relatively low affinity for D2 receptors in the striatum, while
its in vitro affinity for the D4 receptors is approximately ten times greater
than that for D2 receptors, and it has also been shown to bind to the D1, D3
and D5 receptors. Since D4 density is highest in the frontal cortex and
amygdala but relatively low in the basal ganglia, this may be the explanation
for the efficacy of clozapine in alleviating the symptoms of schizophrenia
without causing extra-pyramidal side-effects. Clozapine has been recognised to
show significant activity at a broad range of receptors outside the DA system.
Of particular interest is its high affinity for 5-HT receptors, including
5-HT2, 5-HT3, 5-HT6 and 5-HT7 subtypes. Clozapine has high affinities for
muscarinic A1 and A2 receptors, while it also has significant effects on
GABA-ergic and glutamatergic mechanisms.
Pharmacokinetics
and Metabolism
After oral administration the drug is rapidly absorbed. There is extensive
first-pass metabolism and only 27-50% of the dose reaches the systemic circulation
unchanged.
Its plasma concentration has been observed to vary from patient to patient.
Various individual factors may vary response such as smoking, hepatic
metabolism, gastric absorption, age and, possibly, gender. Clozapine is rapidly
distributed. It crosses the blood-brain barrier and is distributed in breast
milk. It is 95% bound to plasma proteins. Steady-state plasma concentration is
reached after 7-10 days. The onset of the anti-psychotic effect can take
several weeks, but maximum effect may require several months. In
treatment-resistant schizophrenia, patients have been reported to continue to
improve for at least two years after the start of clozapine treatment.
Clozapine metabolises into various metabolites, out of which only norclozapine
(a desmethyl metabolite) is pharmacologically active. The other metabolites do
not appear to have clinically significant activity. Its plasma concentration
declines in the biphasic manner, typical of oral anti-psychotics, and its mean
elimination half-life ranges from 6 to 33 hours. About 50% of a dose is
excreted in urine and 30% in the faeces.
Cautions and Contra-indications
These include patients with
myeloproliferative disorders, a history of toxic or idiosyncratic
agranulocytosis or severe granulocytopaenia (with the exception of
granulocytopaenia/agranulocytosis from previous chemotherapy). Clozapine is
contra-indicated in patients with active liver disease, progressive liver
disease and hepatic failure. Other contra-indications include severe CNS
depression or comatose state, severe renal and cardiac disease, uncontrolled
epilepsy, circulatory collapse, alcoholic/toxic psychosis and previous
hypersensitivity to clozapine.
The most serious of clozapine's
side-effects is agranulocytosis. Other important side-effects include postural
hypotension and tachycardia, sedation, seizures, weight gain and rebound
psychosis.
Clozapine can also cause:
Isolated reports have been
documented of clozapine-associated emergence of obsessive compulsive symptoms[46,47] , priapism[48,49] , allergic complications[50,51] . pancreatitis[52] , toxic hepatitis[53] , elevation in creatinine kinase levels[54] and diabetes-like symptoms[55,56] .
There have also been a handful of
papers and case reports linking clozapine with raised triglyceride levels.
Ghaeli and Dufresne[57] found that elevated serum triglycerides in four patients resolved when
they were switched to risperidone. In two of these patients clozapine was
re-introduced and again serum triglycerides increased. They called for serum
triglyceride levels to be monitored in clozapine patients with additional
cardiac risk factors. Dursun et al.[58] looked at cholesterol and related lipids in eight patients on clozapine
treatment over 12 weeks. Serum triglyceride levels were found to increase, but
not cholesterol levels.
The therapeutic armamentarium for the treatment of schizophrenia has grown
and diversified in the half century since the advent of chlorpromazine and the
beginning of the pharmacologic era in psychiatry. Over the past decade, much of
our attention regarding the treatment for schizophrenia and related psychotic
disorders has focused on a new class of antipsychotic medications. The
reintroduction of clozapine represented a major step forward, and led to the
proliferation of 'atypical' or second-generation antipsychotics
(SGAs), including risperidone,
olanzapine, quetiapine, ziprasidone, sertindole and zotepine. In fact, there is
growing evidence that most of the new medications can offer some advantages over
'typical' or first-generation antipsychotics (FGAs) such as greater improvement in negative symptoms, cognitive impairment,
relapse prevention, functional capacity, and quality of life with fewer
extrapyramidal symptoms (EPS), and less tardive dyskinesia (TD) (for a review, see Miyamoto et al1). Accordingly, many clinicians are prescribing these new antipsychotics as
first-line agents for acute and maintenance therapy for schizophrenia.2, 3, 4, 5 However, these advantages, thus far, have been regarded as incremental and
not necessarily substantial. In addition, concerns about side effects such as
EPS have been replaced by other distressing side effects, including weight gain,
hyperglycemia and dyslipidemia. At present, we are still in the process of
defining fully the clinical profiles of new agents in terms of the extent of
their therapeutic efficacy and adverse effects, on a variety of other outcomes
including cognition, affect, suicide, subjective response, social and
vocational function, cost effectiveness, etc.6
First-generation
antipsychotic agents
The effect that
is common to all FGAs is a high affinity for dopamine D2 receptors,17 and there is a strong correlation between the therapeutic doses of these
drugs and their binding affinity for the D2 receptor.18, 19, 20, 21 In vitro data show that FGAs such as haloperidol bind 'tightly' to
the D2 receptor and dissociate slowly.22 In vivo positron emission tomography (PET) and single photon
emission computed tomography (SPECT) studies have further demonstrated the
importance of dopamine receptor occupancy as a predictor of antipsychotic
response and adverse effects (for a review, see Remignton and Kapur23). Such studies have demonstrated that antipsychotic effects are associated
with a striatal D2 receptor occupancy of 65–70%,24, 25, 26, 27 and D2 occupancy greater than 80% significantly increases the
risk of EPS.24 Recent imaging studies have also shown that therapeutic doses of FGAs
produce high blockade of D2-like receptors equally in limbic
cortical areas and the striatum.28, 29 Thus, a threshold between 65 and 80% D2 occupancy appears to
represent the therapeutic window to minimize the risk of EPS for FGAs.23, 27, 30 However, this is not absolute as some patients can respond below this
threshold, and nonresponders can be seen in spite of adequate D2
receptor blockade reflecting the limitations of the receptor occupancy model.27, 31 Interestingly, low doses of haloperidol (2–5 mg/day) would be expected to
induce 60–80% dopamine D2 receptor occupancy,25, 32 while dosages five to 20 times as high are often prescribed in current
clinical practice.33 This may be partly accounted for by the fact that long-term treatment with
FGAs induces upregulation in D2 receptors in both animals34, 35 and humans,36, 37 which appears to be associated with dopamine D2-mediated
supersensitivity,38, 39 thus theoretically, increments in dose may be needed to produce the same
effect on dopaminergic transmission for chronic patients.27, 31
It is important to acknowledge that the gradual and time-dependant onset of
therapeutic efficacy is not consistent with the rapid striatal D2
receptor blockade induced by antipsychotics. Preclinical studies demonstrating
that chronic treatment of rodents with FGAs can decrease the number of
spontaneously active dopamine neurons in both the substantia nigra pars
compacta (A9) and the ventral tegmental area (A10) have given rise to the
'depolarization inactivation (or block) hypothesis'.40, 41, 42 Mereu et al,43, 44, 45 however, have suggested that the depolarization inactivation of dopamine
neurons may be an artifact produced by the use of general anesthetics, and
thereby questioned the validity of this phenomenon and whether it would occur
in the intact nonanesthetized unrestrained animals.43, 44, 45 Nevertheless, a number of studies have demonstrated that FGA-induced
dopamine cell depolarization block does occur in nonanesthetized animals40, 41, 46, 47 (for a review, see Grace et al48).
Benzamides
Amisulpride, a substituted benzamide analogue of sulpiride, is a highly selective
anatagonist of D2 and D3 receptors with little affinity
for D1-like or nondopaminergic receptors (Table ).49, 50 Its congener, sulpiride, demonstrates a generally similar pharmacological
profile. Preclinical studies suggest that low doses of amisulpride (and
probably sulpiride) preferentially block presynaptic D2-like
autoreceptors, and thus lead to an increase in dopaminergic release and
neurotransmission, while higher doses reduce certain postsynaptic dopamine
receptor-mediated behaviors that predict antipsychotic efficacy, but with
little or no induction of catalepsy that predicts low EPS liability.31, 50, 51 Several PET and SPECT studies in schizophrenia demonstrated that
amisulpride selectively binds to temporal cortical D2/D3
receptors in a dose-dependent fashion, but this extra-striatal selectivity is
lost at higher doses as striatal D2/D3 receptor occupancy
increases.52, 53, 54 Another PET study found no significant binding to 5-HT2A
receptors in amisulpride-treated patients.55 It is also characterized by the rapid dissociation from the D2
receptor similar to clozapine.56 Amisulpride is essentially devoid of 5-HT2A antagonism, thus
its moderate affinity for striatal D2 receptors and preferential
occupancy of limbic cortical D2/D3 receptors may be
reasons for its therapeutic efficacy and low liability to induce EPS.54
Second-generation
antipsychotic agents
The
serotonin–dopamine antagonism theory
The 'serotonin–dopamine (S2/D2)
antagonism theory' promulgated by Meltzer et al57 suggests that a higher ratio of a drug's affinity for serotonin 5-HT2A
receptor relative to dopamine D2 receptor affinity can predict 'atypicality'
and will explain the enhanced efficacy and reduced EPS liability of SGAs (for
reviews, see Miyamato et al,1 Lieberman,58 Duncan et al59).
PET studies showing that therapeutic doses of risperidone, olanzapine and ziprasidone produce greater than 70%
occupancy of D2 receptors suggest that a specific threshold of D2
receptor antagonism could be important in producing antipsychotic effects of
these drugs.60, 61, 391 Clozapine and quetiapine, however, exhibit lower levels of D2
receptor occupancy (less than 70%) at therapeutically effective doses (Table),24, 61, 62, 63 suggesting that a threshold level of D2 receptor occupancy (and
possibly antagonism) alone cannot fully explain the greater therapeutic
efficacy of clozapine59 or for that matter serve as a model to predict antipsychotic efficacy. The
low occupancy of striatal D2 receptors by clozapine and quetiapine
could account for its low EPS liability.30, 62, 63, 64 Interestingly, ziprasidone exhibits high levels of D2 occupancy
at doses of 20–40 mg,65, 66 doses that are substantially below the therapeutically effective dose
range (120–200 mg/day).67, 68 Thus, pharmacological properties other than a threshold level of D2
receptor antagonism (at least as reflected by receptor occupancy levels) may
account for the clinical efficacy of ziprasidone.
Clozapine, risperidone, olanzapine and ziprasidone
occupy more than 80% of cortical 5-HT2A receptors in the therapeutic
dose range in humans (Table
1).24, 60, 61, 63, 69, 70 Although 5-HT2A receptor antagonism is likely to be associated
with the low EPS liability of SGAs, risperidone at higher doses produces EPS,71 indicating that high levels of D2. antagonism cannot be
completely ameliorated by even maximal 5-HT2A receptor antagonism.
Moreover, at this point, it is unclear what clinical effects 5-HT2A
antagonism confers, beyond mitigating the adverse effect of striatal D2
antagonism, and propensity to cause EPS.72 In particular, the role of 5-HT2A antagonism in the superior
therapeutic responses to clozapine awaits further clarification.59 The apparent lack of efficacy of monotherapy with the selective potential
role of the 5-HT2A receptor antagonist M-10090773 indicates that 5HT2A antagonism alone cannot explain the
efficacy of SGAs. Further studies examining combination therapy with D2
antagonist and M-100907 are necessary to evaluate the potential role of 5HT2A
antagonism.
The 'fast-off-D2'
theory
To date, there
is no evidence showing that an agent without some degree of D2
binding can act as an effective antipsychotic.6 The question has been do pharmacologic effects on dopamine-mediated
pathways account for all of the clinical therapeutic effects of antipsychotic
drugs. Recent in vitro studies have demonstrated that antipsychotics
dissociate from the D2 receptor at very different rates, expressed
as a koff value.22, 74 The SGAs have higher koff values as a group, that is
faster dissociation rates, than the FGAs, but they differ among themselves on
this dimension as well (e.g., quetiapine >clozapine >olanzapine
>ziprasidone >risperidone).6, 56, 75 Kapur and Seeman hypothesized that dissociation from the D2
receptor quickly makes an antipsychotic agent more accommodating of
physiological dopamine transmission, permitting an antipsychotic effect without
EPS, hyperprolactinemia, as well as conferring benefits along a variety of
clinical dimensions such as cognitive, affective and secondary negative
symptoms.74 Accordingly, they suggest that sustained D2 occupancy is not
necessary for antipsychotic action. However, this theory cannot explain the
greater therapeutic efficacy of clozapine compared with other SGAs,
particularly in the management of treatment-resistant schizophrenia. The rapid
dissociation of clozapine and quetiapine from D2 receptors by
endogenous dopamine may lead to more rapid clinical relapse after
discontinuation of these medications.75 At present, it remains unclear how long an antipsychotic agent must bind
to the D2 receptor to maximize therapeutic efficacy while minimizing
the risk of D2-related side effects.31 Another limitation of this model is that all antipsychotics have not been
studied with it, including the benzamides, low-potency FGAs and partial
dopamine agonists (e.g. aripiprazole).
Potential
therapeutic significance of targeting other neuroreceptors
The SGAs,
particularly clozapine, have multiple sites of action other than dopamine D2
receptors, including dopamine (D1, D3, D4),
serotonin (5-HT1A, 5-HT2C, 5-HT6, 5-HT7),
muscarinic cholinergic and histamine receptor (Table). Among them, it has been hypothesized that the partial agonist activity
of clozapine at serotonin 5-HT1A receptors may contribute to its
efficacy against anxiety, depression, cognitive and negative symptoms of
schizophrenia76, 77, 78, 79 Preclinical studies have also suggested that 5-HT1A agonists
may potentiate the antipsychotic activity of dopaminergic antagonists,80 and activation of inhibitory 5-HT1A autoreceptors may
counteract the induction of EPS due to striatal D2 receptor
blockade.81 Furthermore, 5-HT1A agonism has been suggested to contribute to
enhancement of prefrontal dopamine release.82 Indeed, clozapine, and olanzapine and ziprasidone, but not haloperidol or
risperidone, can preferentially augment dopamine and norepinephrine release in
the prefrontal cortex relative to the subcortical areas, which may be related
to their potential efficacy for negative symptoms and cognitive dysfunction of
schizophrenia.83 The prefrontal cortex contains high densities of 5-HT1A and
5-HT2A receptors located on affrents to and on pyramidal neurons.84 It has been suggested that activation of 5-HT2A receptors
increases the release of glutamate onto pyramidal cells,85 whereas serotonin, possibly via activation of 5-HT1A receptors,
inhibits the release of glutamate.86 Thus, compounds with 5-HT2A antagonism and/or 5-HT1A
agonism like clozapine could regulate the physiological balance between
excitatory and inhibitory inputs onto prefrontal pyramidal neurons.78, 84 Some SGAs, particularly ziprasidone, can also increase serotonin activity
in the frontal cortex by virtue of their affinity for the serotonin
transporter.87, 88 In addition, some of the SGAs, but not FGAs, can increase the release of
acetylcholine in the prefrontal cortex, which could be a possible factor
contributing to improve cognition in schizophrenia.89
Partial dopamine
agonists
Aripiprazole (OPC-14597), approved for clinical use in the US and more recently in
Europe, is the first of a possible 'next- generation antipsychotics' with a
mechanism of action that differs from currently marketed FGAs and SGAs.79 It is
a partial dopamine agonist with a high affinity for D2 and D3 receptors,131,
132, 133 and demonstrates properties of a functional agonist and antagonist in
animal models of dopaminergic hypoactivity and hyperactivity, respectively.131,
134 Aripiprazole acts on both postsynaptic D2 receptors and presynaptic
autoreceptors. Partial agonist activity at D2 receptors could stabilize the
dopamine system while avoiding the hypodopaminergia that may limit the efficacy
and tolerability of FGAs.135 In addition, aripiprazole displays 5-HT1A partial
agonism and 5-HT2A antagonism.136 The distinction, pharmacologically, between
aripiprazole and the SGAs in this regard is that aripiprazole's affinity for
the D2 receptors exceeds that for serotonin by an order of magnitude.6, 137 It
also has very modest affinity for alpha1-adrenergic, histamine (H1), 5-HT6, and
5-HT7 receptors, and no appreciable affinity for D1, histaminergic or
cholinergic muscarinic receptors (Table 1).132, 137 The clinical significance
of these in vitro receptor-binding affinities as well as its partial 5-HT1A
agonism has not been determined apart from their obvious association with side
effects.138 It has also been proposed that aripiprazole induces 'functionally
selective' activation of D2 receptors coupled to diverse G proteins (and hence
different functions), thereby explaining its unique clinical effects.132, 137
Aripiprazole neither conforms to the standard 5-HT2A/D2 antagonist nor the fast
dissociation theories of atypicality. It has a very high affinity for the D2
receptor (greater than its 5-HT2A affinity) and this is unlikely to have a fast
koff. Similarly, the compound has a long half-life and is therefore unlikely to
show transient receptor occupancy. PET studies in normal humans indicate that
although aripiprazole occupies up to 90% of striatal D2-like dopamine receptors
at clinical doses, it does not cause EPS, suggesting that its inherent agonism
may provide a mechanism that protects against excessive blockade of the D2
system.139 This underlines aripiprazole's unique mechanism of action as a
partial dopamine receptor agonist,79, 134 and possibly a novel form of
treatment for schizophrenia.
Therapy of
Schizophrenia
Schizophrenia is an endogenous psychosis of episodic character. Its chief
symptoms reflect a thought disorder (i.e., distracted, incoherent, illogical
thinking; impoverished intellectual content; blockage of ideation; abrupt
breaking of a train of thought: claims of being subject to outside agencies
that control the patient’s thoughts), and a disturbance of affect (mood
inappropriate to the situation) and of psychomotor drive. In addition, patients
exhibit delusional paranoia (persecution mania) or hallucinations (fearfulness
hearing of voices). Contrasting these “positive” symptoms, the so-called
“negative” symptoms, viz., poverty of thought, social withdrawal, and
anhedonia, assume added importance in determining the severity of the disease.
The disruption and incoherence of ideation is symbolically represented at the
top left (A) and the normal psychic state is illustrated.
The term antipsychotic is applied to a group of drugs used to treat
psychosis. Common conditions with which antipsychotics might be used include
schizophrenia, mania and delusional disorder, although antipsychotics might be
used to counter psychosis associated with a wide range of other diagnoses.
Antipsychotics also have some effects as mood stabilizers, leading to their
frequent use in treating mood disorder (particularly bipolar disorder) even
when no signs of psychosis are present. Some antipsychotics (haloperidol,
pimozide) are used off-label to treat Tourette syndrome.
Antipsychotics are also referred to as neuroleptic drugs, or simply
neuroleptics. The word neuroleptic is derived from Greek; neuro refers to the
nerves and lept means "to take hold of". Thus the word means
"taking hold of one's nerves", which implies their role in mood
stabilization.
There are currently two main types of antipsychotics in use, the typical
antipsychotics and atypical antipsychotics. A new class of antipsychotic drugs
has recently been discovered, known as dopamine partial agonists. Clinical
development has progressed rapidly on partial dopamine agonists, and one drug
in this class (aripiprazole) has already been approved by the Food and Drug
Administration. Although the underlying mechanism of this new class is
different from all previous typical and atypical antipsychotics, dopamine
partial agonists are often categorized as atypicals.
Typical antipsychotics are sometimes referred to as major tranquilizers,
because some of them can tranquilize and sedate. This term is increasingly
disused because many newer antipsychotics do not have strong sedating
properties and the terminology implies a connection with benzodiazepines when
none exists.
Neuroleptics After administration of a neuroleptic, there is at first only
psychomotor dampening. Tormenting paranoid ideas and hallucinations lose their
subjective importance dimming of flashy colors); however, the psychotic
processes still persist. In the course of weeks, psychicprocesses gradually
normalize; the psychotic episode wanes, although complete normalization often
cannot be achieved because of the persistence of negative symptoms.
Nonetheless, these changes are significant because the patient experiences
relief from the torment of psychotic personality changes; care of the atient is
made easier and return to a familiar community environment is accelerated.
The range of interactions can produce different adverse effects including
extrapyramidal reactions, including acute dystonias, akathisia, parkinsonism
(rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence,
lethargy, seizures, and hyperprolactinaemia.
The atypical antipsychotics (especially olanzapine) seem to cause weight
gain more commonly than the typical antipsychotics. The well documented
metabolic side effects associated with weight gain include diabetes that, not
infrequently, can be life threatening.
Clozapine also has a risk of inducing agranulocytosis, a potentially
dangerous reduction in the number of white blood cells in the body. Because of
this risk, patients prescribed clozapine may need to have regular blood checks
to catch the condition early if it does occur, so the patient is in no danger.
One of the more serious of these side effects is tardive dyskinesia, in
which the sufferer may show repetitive, involuntary, purposeless movements
often of the lips, face, legs or torso. It is believed that there is a greater
risk of developing tardive dyskinesia with the older, typical antipsychotic
drugs, although the newer antipsychotics are now also known to cause this disorder.
It is believed by some that the risk of tardive dyskinesia can be reduced by
combining the anti-psychotics with diphenhydramine or benztropine, though this
has not been established. Central nervous system damage is also associated with
irreversible tardive akathisia and/or tardive dysphrenia.
A potentially serious side effect of many antipsychotics is that they tend
to lower an individuals seizure threshold. Chlorpromazine and clozapine
particularly, have a relatively high seizurogenic potential. Fluphenazine,
haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution
should be exercised in individuals that have a history of seizurogenic
conditions (such as epilepsy, or brain damage).
Another serious side effect is neuroleptic malignant syndrome, in which the
drugs appear to cause the temperature regulation centers to fail, resulting in
a medical emergency as the patient's temperature suddenly increases to
dangerous levels.
Another problematic side effect of antipsychotics is dysphoria, meaning
that it just makes the patient feel bad. This side-effect is a major problem
for patients with schizophrenia in that it causes them to discontinue
medication, and this produces a relapse of psychotic symptoms.
Whilst this may seem a daunting list, it must be noted that some people
suffer few of the obvious side effects from taking antipsychotic medication.
Some side effects, such as subtle cognitive problems, may go unnoticed.
Other symptoms of akinesia of antipsychotics include deterioration of teeth
due to a lack of saliva. The link between such symptoms and the use of
antipsychotics is often overlooked.
While the atypical, second-generation medications were marketed as offering
greater efficacy in reducing psychotic symptoms while reducting side effects
(and extra-pyramidal symptoms in particular) than typical medications, these
results showing these effects often lack robustness. To remediate this problem,
the NIMH conducted a recent multi-site, double-blind, study (the CATIE
project), which was published in 2005. A phase 2 part of this study roughly
replicated these findings.
The conventional (or classical) neuroleptics comprise two classes of
compounds with distinctive chemical structures: 1. the phenothiazines derived
from the antihistamine promethazine(prototype: chlorpromazine), including their
analogues (e.g., thioxanthenes); and 2. the butyrophenones (prototype:
haloperidol). According to the chemical structure of the side chain,
phenothiazines and thioxanthenes can be subdivided into aliphatic
(chlorpromazine, triflupromazine, and piperazine congeners (trifluperazine,
fluphenazine, flupentixol). The antipsychotic effect is probably due to an
antagonistic action at dopamine receptors. Aside from their main antipsychotic
action, neuroleptics display additional actions owing to their antagonism at –
muscarinic acetylcholine receptors _ atropine-like effects; – б-adrenoceptors
for norepinephrine _ disturbances of blood pressure regulation; – dopamine
receptors in the nigrostriatal system _ extrapyramidal motordisturbances; in
the area postrema _ antiemetic action, and in the pituitary gland _increased
secretion of prolactin; – histamine receptors in the cerebral cortex _ possible
cause of sedation. These ancillary effects are also elicited in healthy
subjects and vary in intensity among individual substances. Other indications.
Acutely, there is sedation with anxiolysis after neuroleptization has been
started. This effect can be utilized for: “psychosomatic uncoupling” in
disorders with a prominent psychogenic component; neuroleptanalgesia by means
of the butyrophenone droperidol in combination with an opioid; tranquilization
of overexcited, agitated patients; treatment of delirium tremens with
haloperidol; as well as the control of mania. It should be pointed out that
neuroleptics do not exert an anticonvulsant action, on the contrary, they may
lower seizure thershold.
Because they inhibit the thermoregulatory center, neuroleptics can be
employed for controlled hypothermia. Adverse Effects. Clinically most important
and therapy-limiting are extrapyramidal disturbances; these result from
dopamine receptor blockade. Acute dystonias occur immediately after
neuroleptization and are manifested by motor impairments, particularly in the
head, neck, and shoulder region. After several days to months, a parkinsonian
syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop.
All these disturbances can be treated by administration of antiparkinson drugs
of the anticholinergic type, such as biperiden (i.e., in acute dystonia). As a
rule, these disturbances disappear after withdrawal of neuroleptic medication.
Tardive dyskinesia may become evident after chronic neuroleptization for
several years, particularly when the drug is discontinued. It is due to
hypersensitivity of the dopamine receptor system and can be exacerbated by
administration of anticholinergics. Chronic use of neuroleptics can, on
occasion, give rise to hepatic damage associated with cholestasis. A very rare,
but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal
muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of
intensive countermeasures (including treatment with dantrolene). Neuroleptic
activity profiles. The marked differences in action spectra of the
phenothiazines, their derivatives and analogues, which may partially resemble
those of butyrophenones, are important in determining therapeutic uses of
neuroleptics. Relevant parameters include: antipsychotic efficacy (symbolized by
the arrow); the extent of sedation; and the ability to induce extrapyramidal
adverse effects. The latter depends on relative differences in antagonism
towards dopamine and acetylcholine, respectively. Thus, the butyrophenones
carry an increased risk of adverse motor reactions because they lack
anticholinergic activity and, hence, are prone to upset the balance between
striatal cholinergic and dopaminergic activity.
Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphenazine) have greater antipsychotic potency
than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflupromazine). However, their antipsychotic
effects are qualitatively indistinguishable. As structural analogues of the
phenothiazines, thioxanthenes (e.g., chlorprothixene, flupentixol) possess a
central nucleus in which the N atom is replaced by a carbon linked via a double
bond to the side chain. Unlike the phenothiazines, they display an added
thymoleptic activity. Clozapine is the prototype of the so-called atypical
neuroleptics, a group that combines a relative lack of extrapyramidal adverse
effects with superior efficacy in alleviating negative symptoms. Newer members
of this class include risperidone, olanzapine, and sertindole. Two
distinguishing features of these atypical agents are a higher affinity for
5-HT2 (or 5-HT6) receptors than for dopamine D2 receptors and relative
selectivity for mesolimbic, as opposed to nigrostriatal, dopamine neurons.
Clozapine also exhibits high affinity for dopamine receptors of the D4 subtype,
in addition to H1 histamine and muscarinic acetylcholine receptors. Clozapine
may cause dose–dependent seizures and agranulocytosis, necessitating close
hematological monitoring. It is strongly sedating. When esterified with a fatty
acid, both fluphenazine and haloperidol can be applied intramuscularly as depot
preparations.
Lithium ions
Lithium salts (e.g., acetate, carbonate) are effective in controlling the
manic phase. The effect becomes evident approx. 10 d after the start of
therapy. The small therapeutic index necessitates frequent monitoring of Li+
serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting
morning blood samples. At higher values there is a risk of adverse effects. CNS
symptoms include fine tremor, ataxia or seizures. Inhibition of the renal
actions of vasopressin leads to polyuria and thirst. Thyroid function is
impaired, with compensatory development of (euthyroid) goiter. The mechanism of
action of Li ions remains to be fully elucidated. Chemically, lithium is the
lightest of the alkali metals, which include such biologically important
elements as sodium and potassium. Apart from interference with transmembrane
cation fluxes (via ion channels and pumps), a lithium effect of major
significance appears to be membrane depletion of phosphatidylinositol
bisphosphates, the principal lipid substrate used by various receptors in
transmembrane signalling. Blockade of this important signal transduction
pathway leads to impaired ability of neurons to respond to activation of
membrane receptors for transmitters or other chemical signals. Another site of
action of lithium may be GTP-binding proteins responsible for signal
transduction initiated by formation of the agonist- receptor complex. Rapid
control of an acute attack of mania may require the use of a neuroleptic.
Benzodiazepines
Benzodiazepines modify affective responses to sensory
perceptions; specifically, they render a subject indifferent towards anxiogenic
stimuli, i.e., anxiolytic action. Furthermore, benzodiazepines exert sedating,
anticonvulsant, and muscle-relaxant (myotonolytic) effects. All
these actions result from augmenting the activity of inhibitory neurons and
are mediated by specific benzodiazepine receptors that form an integral
part of the GABAA receptor- chloride channel complex. The inhibitory
transmitter GABA acts to open the membrane chloride channels.
Increased chloride
conductance of the neuronal membrane effectively shortcircuits responses to
depolarizing inputs. Benzodiazepine receptor agonists increase the affinity of GABA to its
receptor. At a given concentration of GABA, binding to the receptors will,
therefore, be increased, resulting in an augmented response. Excitability of
the neurons is diminished. Therapeutic indications for benzodiazepines include anxiety
states associated with neurotic, phobic, and depressive disorders, or myocardial infarction (decrease in
cardiac stimulation
due to anxiety); insomnia; preanesthetic (preoperative) medication; epileptic
seizures; and hypertonia of skeletal musculature (spasticity, rigidity).
Since GABA-ergic synapses are confined to neural tissues, specific inhibition
of central nervous functions can be achieved; for instance, there is little
change in blood pressure, heart rate, and body temperature. The therapeutic
index of benzodiazepines, calculated with reference to the toxic dose producing
respiratory depression, is greater than 100 and thus exceeds that of
barbiturates and other sedative-hypnotics by more than tenfold. Benzodiazepine
intoxication can be treated with a specific antidote (see below). Since benzodiazepines
depress responsivity to external stimuli, automotive driving skills and other
tasks requiring precise sensorimotor coordination will be impaired. Triazolam
(t1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory
(anterograde amnesia) and to cause rebound anxiety or insomnia and daytime
confusion. The severity of these and other adverse reactions (e.g., rage,
violent hostility, hallucinations), and their increased frequency in the
elderly, has led to curtailed or suspended use of triazolam in some countries
(UK). Although benzodiazepines are well tolerated, the possibility of
personality changes (nonchalance, paradoxical excitement) and the risk of
physical dependence with chronic use must not be overlooked. Conceivably,
benzodiazepine dependence results from a kind of habituation, the functional
counterparts of which become manifest during abstinence as restlessness and
anxiety; even seizures may occur. These symptoms reinforce chronic ingestion of
benzodiazepines. Benzodiazepine antagonists, such as flumazenil, possess
affinity for benzodiazepine receptors, but they lack intrinsic activity.
Flumazenil is an effective antidote in the treatment of benzodiazepine
overdosage or can be used postoperatively to arouse patients sedated with a
benzodiazepine. Whereas benzodiazepines possessing agonist activity indirectly
augment chloride permeability, inverse agonists exert an opposite
action. These substances give rise to pronounced restlessness, excitement,
anxiety, and convulsive seizures. There is, as yet, no therapeutic indication
for their use.
Pharmacokinetics of Benzodiazepines All benzodiazepines exert their actions at specific receptors . The choice between different agents is dictated
by their speed, intensity, and duration of action. These, in turn, reflect
physicochemical and pharmacokinetic properties. Individual benzodiazepines
remain in the body for very different lengths of time and are chiefly
eliminated through biotransformation. Inactivation may entail a single chemical
reaction or several steps (e.g., diazepam) before an inactive metabolite
suitable for renal elimination is formed. Since the
intermediary products may, in part, be pharmacologically active and, in part,
be excreted more slowly than the parent substance, metabolites will accumulate
with continued regular dosing and contribute significantly to the final effect.
Biotransformation begins either at substituents on the diazepine ring (diazepam:
N-dealkylation at position 1; midazolam: hydroxylation of the methyl
group on the imidazole ring) or at the diazepine ring itself. Hydroxylated
midazolam is quickly eliminated following glucuronidation (t1/2 ~ 2 h).
N-demethyldiazepam (nordazepam) is biologically active
and undergoes hydroxylation at position 3 on the diazepine ring. The
hydroxylated product (oxazepam) again is pharmacologically active. By virtue of
their long half-lives, diazepam (t1/2 ~ 32 h) and, still more so, its
metabolite, nordazepam (t1/2 50–90 h), are eliminated slowly and accumulate
during repeated intake. Oxazepam undergoes conjugation to glucuronic acid via
its hydroxyl group (t1/2 = 8 h) and renal excretion (A). The range of
elimination half-lives for different benzodiazepines or their active metabolites
is represented by the shaded areas (B).
Substances with a short half-life that are not
converted to active metabolites can be used for induction or maintenance of
sleep (light blue area in B). Substances with a long half-life are
preferable for long-term anxiolytic treatment (light green area) because they
permit maintenance of steady plasma levels with single daily dosing. Midazolam
enjoys use by the i.v. route in preanesthetic medication and anesthetic
combination regimens.
Benzodiazepine Dependence Prolonged regular use of benzodiazepines can lead to
physical dependence. With the long-acting substances marketed initially, this
problem was less obvious in comparison with other dependence- producing drugs
because of the delayed appearance of withdrawal symptoms. The severity of the
abstinence syndrome is inversely related to the elimination t1/2, ranging from
mild to moderate (restlessness, irritability, sensitivity to sound and light,
insomnia,and tremulousness) to dramatic (depression, panic, delirium, grand mal
seizures). Some of these symptoms pose diagnostic difficulties, being
indistinguishable from the ones originally treated. Administration of a
benzodiazepine antagonist would abruptly provoke abstinence signs. There are
indications that substances with intermediate elimination half-lives are most
frequently abused (violet area in B).
Tranquilizers
Tranquilizers are depressant
drugs that slow down the central nervous system (CNS), and thus are similar to
such other CNS depressants as alcohol and barbituates.
The term "major tranquilizer" was formerly
applied to drugs used to treat severe mental illnesses, such as schizophrenia.
However, these drugs are now more commonly called neuroleptics; their action
specifically relieves the symptoms of mental illness, and they are rarely
misused for other purposes. This paper therefore deals with the anti-anxiety
agents, or anxiolytics (formerly called "minor" tranquilizers).
Anti-anxiety agents share many
similiarities with barbituates; both are classified as sedative/hypnotics.
These newer agents were introduced under the term "tranquilizer"
because, it was claimed, they provided a calming effect without sleepiness. Today,
tranquilizers have largely replaced barbiturates in the treatment of both
anxiety and insomnia because they are safer and more effective. The degree of
sleepiness induced depends on the dosage. Tranquilizers are also used as
sedatives before some surgical and medical procedures, and they are sometimes
used medically during alcohol withdrawal.
Although tranquilizers do not exhibit the serious
dependence characteristics of barbiturates, they nevertheless can produce
tolerance and dependence. They may also be misused and abused.
The first drug to be labelled a tranquilizer was
meprobamate - under the trade name Miltown - in 1954. Today, however, the most
popular anti-anxiety agents are the benzodiazepines (e.g. Valium, Halcion, and
Ativan).
The first benzodiazepine developed was
chlordiazepoxide, which is sold under such trade names as Librium and
Novopoxide. The next was diazepam; it is marketed, among other brand names, as
Valium, E-Pam, and Vivol. In the early 1970s diazepam was the most widely
prescribed drug in North America.
Now Halcion and Ativan - drugs from the same family as
diazepam but eliminated more rapidly from the body - account for most benzodiazepine
prescriptions. Some are prescribed as anti-anxiety drugs (e.g. Valium,
Librium); others are recommended as sleeping medications (e.g. Dalmane, Somnol,
Novoflupam, and Halcion).
Effects
The effects of any drug depend on several
factors:
With tranquilizers, a therapeutic dose (i.e. what is
medically prescribed) relieves anxiety and may, in some people, induce a loss
of inhibition and a feeling of well-being. Responses vary, however. Some people
report lethargy, drowsiness, or dizziness. Tranquilizers, though, have very few
side effects.
As the dose of a tranquilizer is increased, so is
sedation and impairment of mental acuity and physical coordination. Lower doses
are recommended for older people or for those with certain chronic diseases,
since their bodies tend to metabolize these drugs more slowly.
Studies show that anti-anxiety agents, even at the
usually recommended and prescribed doses, may disrupt the user's ability to
perform certain physical, intellectual, and perceptual functions. For these
reasons, users should not operate a motor vehicle or engage in tasks calling
for concentration and coordination. Such activities are particularly hazardous
if tranquilizers are used together with alcohol and/or barbiturates (i.e. other
sedative/hypnotics) or antihistamines (in cold, cough, and allergy remedies).
These effects occur early in therapy, however, and wane over time with
increased tolerance (when more of the drug is needed to produce the same effect).
Because some tranquilizers (such as diazepam) are
metabolized quite slowly, residue can accumulate in body tissues with long-
term use and can heighten such effects as lethargy and sluggishness.
Toxic Effects
Tranquilizer overdose,
particularly with benzodiazepines, has become increasingly common since the
1960s. While these drugs are usually safe even when an overdose is taken (death
rarely results from benzodiazepine use alone), they can be fatal in combination
with alcohol and other drugs that depress the central nervous system.
In Canada, as elsewhere, tranquilizer-related
poisonings and overdoses have kept pace with the drug's availability. It is a
fact that the drugs used in suicide attempts are those most widely prescribed
and available. (The majority of these drug-related suicide attempts are by
women under 30.)
Tolerance and Dependence
Because tolerance to the mood-altering effects
of tranquilizers can develop with regular use, higher daily doses become
necessary to maintain the desired effects. Tolerance may occur even at
prescribed doses.
Chronic users may become both psychologically and
physically dependent on tranquilizers.
Psychological dependence exists when a drug is so central to a person's
thoughts, emotions, and activities that the need to continue its use becomes a
craving or compulsion.
With chronic use, especially at higher doses, physical
dependence can also occur. The user's body has adapted to the presence of
the drug and suffers withdrawal symptoms when use is stopped. The frequency and
severity of the withdrawal syndrome depends on the dose, duration of use, and
whether use is stopped abruptly or tapered off. Symptoms range in intensity
from progressive anxiety, restlessness, insomnia, and irritability in mild
cases to delirium and convulsions in severe cases.
Dependence may also occur following long-term
therapeutic use, but withdrawal symptoms in such cases are mild. Patients
complain of gastrointestinal problems, loss of appetite, sleep disturbances,
sweating, trembling, weakness, anxiety, and changes in perception (e.g.
increased sensitivity to light, sound, and smells).
Risk of dependency
increases if tranquilizers are taken regularly for more than a few months,
although problems have been reported within shorter periods. The onset and severity of withdrawal differ between
the benzodiazepines that are rapidly eliminated from the body (e.g. Halcion)
and those that are slowly eliminated (e.g. Valium). In the former case,
symptoms appear within a few hours after stopping the drug and may be more
severe. In the latter case, symptoms usually take a few days to appear.
Tranquilizers and Pregnancy
If a woman uses tranquilizers regularly, the drug can affect
the baby for up to 10 days after birth. Babies may exhibit the withdrawal
symptoms common to such other depressant drugs as alcohol and barbituates.
These symptoms include feeding difficulties, disturbed sleep, sweating,
irritability, and fever. Symptoms will be more severe if the doses the mother
took are higher.
Administration of diazepam during labor has been
linked to decreased responsiveness and respiratory problems in some newborns.
Hypnotic agents. Antiepileptic drugs
During sleep, the brain generates
a patterned rhythmic activity that can be monitored by means of the
electroencephalogram (EEG). Internal sleep cycles recur 4 to 5 times per night,
each cycle being interrupted by a Rapid Eye Movement (REM)
sleep phase (A). The REM stage is characterized by EEG activity similar
to that seen in the waking state, rapid eye movements, vivid dreams, and
occasional twitches of individual muscle groups against a background of
generalized atonia of skeletal musculature. Normally, the REM stage is entered
only after a preceding non-REM cycle. Frequent interruption of sleep will,
therefore, decrease the REM portion. Shortening of REM sleep
(normally approx. 25% of total sleep duration) results in increased
irritability and restlessness during the daytime. With undisturbed night
rest, REM deficits are compensated by increased REM sleep on subsequent nights (B).
Hypnotics fall into different categories, including
the benzodiazepines (e.g., triazolam, temazepam, clotiazepam, nitrazepam), barbiturates (e.g., hexobarbital, pentobarbital),
chloral hydrate, and H1-antihistamines with sedative activity. Benzodiazepines
act at specific receptors. The site and mechanism of action of barbiturates,
antihistamines, and chloral hydrate are incompletely understood. All hypnotics
shorten the time spent in the REM stages (B).
With repeated ingestion of a
hypnotic on several successive days, the proportion of time spent in REM vs.
non-REM sleep returns to normal despite continued drug intake. Withdrawal of
the hypnotic drug results in REM rebound, which tapers off only over many days (B).
Since REM stages are associated with vivid dreaming, sleep with excessively
long REM episodes is experienced as unrefreshing. Thus, the attempt to
discontinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic
drug dependence.
Depending on their blood levels, both benzodiazepines
and barbiturates produce calming and sedative effects, the former
group also being anxiolytic. At higher dosage, both groups promote
the onset of sleep or induce it (C).
Unlike barbiturates, benzodiazepine
derivatives administered orally lack a general anesthetic action; cerebral
activity is not globally inhibited (respiratory paralysis is virtually
impossible) and autonomic functions, such as blood pressure, heart rate, or
body temperature, are unimpaired. Thus, benzodiazepines possess a therapeutic
margin considerably wider than that of barbiturates. Zolpidem (an
imidazopyridine) and zopiclone (a cyclopyrrolone) are hypnotics that,
despite their different chemical structure, possess agonist activity at the benzodiazepine
receptor.
Due to their narrower margin
of safety (risk of misuse for suicide) and their potential to produce physical
dependence, barbiturates are no longer or only rarely used as hypnotics.
Dependence on them has all the characteristics of an addiction. Because of
rapidly developing tolerance, choral hydrate is suitable only for
short-term use. Antihistamines are popular as nonprescription (over-the-counter)
sleep remedies (e.g., diphenhydramine, doxylamine), in which case their
sedative side effect is used as the principal effect.
Sleep–Wake Cycle and Hypnotics
The physiological mechanisms regulating the sleep-wake
rhythm are not completely known. There is evidence that histaminergic,
cholinergic, glutamatergic, and adrenergic neurons are more active during
waking than during the NREM sleep stage. Via their ascending thalamopetal
projections, these neurons excite thalamocortical pathways and inhibit
GABA-ergic neurons. During sleep, input from the brain stem decreases, giving
rise to diminished thalamocortical activity and disinhibition of the GABA
neurons (A).
The shift in balance between excitatory (red) and
inhibitory (green) neuron groups underlies a circadian change in sleep propensity,
causing it to remain low in the morning, to increase towards early afternoon
(midday siesta), then to decline again, and finally to reach its peak before
midnight (B1).
Treatment of sleep
disturbances. Pharmacotherapeutic
measures are indicated only when causal therapy has failed. Causes of insomnia
include emotional problems (grief, anxiety, “stress”), physical complaints
(cough, pain), or the ingestion of stimulant substances (caffeine-containing
beverages, sympathomimetics, theophylline, or certain antidepressants). As
illustrated for emotional stress (B2), these factors cause an imbalance
in favor of excitatory influences. As a result, the interval between going to
bed and falling asleep becomes longer, total sleep duration decreases, and sleep
may be interrupted by several waking periods. Depending on the type of
insomnia, benzodiazepines with short or intermediate duration of action are
indicated,e.g., triazolam and brotizolam (t1/2 ~ 4–6
h); lormetazepam or temazepam (t1/2 ~ 10–15 h). These drugs shorten the latency
of falling asleep, lengthen total sleep duration, and reduce the frequency of
nocturnal awakenings. They act by augmenting inhibitory activity. Even with the
longer-acting benzodiazepines, the patient awakes after about 6–8 h of sleep,
because in the morning excitatory activity exceeds the sum of physiological and
pharmacological inhibition (B3). The drug effect may, however, become
unmasked at daytime when other sedating substances (e.g., ethanol) are ingested
and the patient shows an unusually pronounced response due to a synergistic
interaction (impaired ability to concentrate or react). As the margin between
excitatory and inhibitory activity decreases with age, there is an increasing
tendency towards shortened daytime sleep periods and more frequent interruption
of nocturnal sleep (C).
Use of a hypnotic drug should
not be extended beyond 4 wk, because tolerance may develop. The risk of a
rebound decrease in sleep propensity after drug withdrawal may be avoided by
tapering off the dose over 2 to 3 wk. With any hypnotic, the risk of suicidal
overdosage cannot be ignored. Since benzodiazepine intoxication may become
life-threatening only when other central nervous depressants (ethanol) are
taken simultaneously and can, moreover, be treated with specific benzodiazepine
antagonists, the benzodiazepines should be given preference as sleep remedies
over the all but obsolete barbiturates.
Benzodiazepines
Benzodiazepines modify
affective responses to sensory perceptions; specifically, they render a subject
indifferent towards anxiogenic stimuli, i.e., anxiolytic action.
Furthermore, benzodiazepines exert sedating, anticonvulsant, and muscle-relaxant
(myotonolytic) effects. All these actions result from augmenting the
activity of inhibitory neurons and are mediated by specific benzodiazepine
receptors that form an integral part of the GABAA receptor- chloride
channel complex. The inhibitory transmitter GABA acts to open the membrane chloride
channels.
Increased chloride
conductance of the neuronal membrane effectively shortcircuits responses to
depolarizing inputs. Benzodiazepine receptor agonists increase the affinity of GABA to its
receptor. At a given concentration of GABA, binding to the receptors will,
therefore, be increased, resulting in an augmented response. Excitability of
the neurons is diminished. Therapeutic indications for benzodiazepines include anxiety
states associated with neurotic, phobic, and depressive disorders, or
myocardial infarction (decrease in cardiac stimulation due to anxiety); insomnia;
preanesthetic (preoperative) medication; epileptic seizures; and hypertonia
of skeletal musculature (spasticity, rigidity). Since GABA-ergic
synapses are confined to neural tissues, specific inhibition of central nervous
functions can be achieved; for instance, there is little change in blood
pressure, heart rate, and body temperature. The therapeutic index of
benzodiazepines, calculated with reference to the toxic dose producing
respiratory depression, is greater than 100 and thus exceeds that of barbiturates
and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication
can be treated with a specific antidote (see below). Since benzodiazepines
depress responsivity to external stimuli, automotive driving skills and other
tasks requiring precise sensorimotor coordination will be impaired. Triazolam
(t1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory
(anterograde amnesia) and to cause rebound anxiety or insomnia and daytime
confusion. The severity of these and other adverse reactions (e.g., rage,
violent hostility, hallucinations), and their increased frequency in the
elderly, has led to curtailed or suspended use of triazolam in some countries (
Benzodiazepine antagonists, such as flumazenil, possess affinity for
benzodiazepine receptors, but they lack intrinsic activity. Flumazenil is an
effective antidote in the treatment of benzodiazepine overdosage or can be used
postoperatively to arouse patients sedated with a benzodiazepine. Whereas
benzodiazepines possessing agonist activity indirectly augment chloride permeability,
inverse agonists exert an opposite action. These substances give rise to
pronounced restlessness, excitement, anxiety, and convulsive seizures. There
is, as yet, no therapeutic indication for their use.
Pharmacokinetics of Benzodiazepines All benzodiazepines exert their actions at specific receptors . The choice between different agents is dictated
by their speed, intensity, and duration of action. These, in turn, reflect
physicochemical and pharmacokinetic properties. Individual benzodiazepines remain
in the body for very different lengths of time and are chiefly eliminated
through biotransformation. Inactivation may entail a single chemical reaction
or several steps (e.g., diazepam) before an inactive metabolite suitable for
renal elimination is formed. Since the intermediary
products may, in part, be pharmacologically active and, in part, be excreted
more slowly than the parent substance, metabolites will accumulate with
continued regular dosing and contribute significantly to the final effect. Biotransformation
begins either at substituents on the diazepine ring (diazepam: N-dealkylation
at position 1; midazolam: hydroxylation of the methyl group on the
imidazole ring) or at the diazepine ring itself. Hydroxylated midazolam is
quickly eliminated following glucuronidation (t1/2 ~ 2 h).
N-demethyldiazepam (nordazepam) is biologically active
and undergoes hydroxylation at position 3 on the diazepine ring. The
hydroxylated product (oxazepam) again is pharmacologically active. By virtue of
their long half-lives, diazepam (t1/2 ~ 32 h) and, still more so, its
metabolite, nordazepam (t1/2 50–90 h), are eliminated slowly and accumulate
during repeated intake. Oxazepam undergoes conjugation to glucuronic acid via
its hydroxyl group (t1/2 = 8 h) and renal excretion (A). The range of
elimination half-lives for different benzodiazepines or their active
metabolites is represented by the shaded areas (B).
Substances with a short half-life that are not
converted to active metabolites can be used for induction or maintenance of
sleep (light blue area in B). Substances with a long half-life are
preferable for long-term anxiolytic treatment (light green area) because they
permit maintenance of steady plasma levels with single daily dosing. Midazolam
enjoys use by the i.v. route in preanesthetic medication and anesthetic
combination regimens.
Benzodiazepine Dependence Prolonged regular use of benzodiazepines can lead to
physical dependence. With the long-acting substances marketed initially, this
problem was less obvious in comparison with other dependence- producing drugs
because of the delayed appearance of withdrawal symptoms. The severity of the
abstinence syndrome is inversely related to the elimination t1/2, ranging from
mild to moderate (restlessness, irritability, sensitivity to sound and light,
insomnia,and tremulousness) to dramatic (depression, panic, delirium, grand mal
seizures). Some of these symptoms pose diagnostic difficulties, being
indistinguishable from the ones originally treated. Administration of a
benzodiazepine antagonist would abruptly provoke abstinence signs. There are
indications that substances with intermediate elimination half-lives are most
frequently abused (violet area in B).
Tranquilizers
Tranquilizers are depressant
drugs that slow down the central nervous system (CNS), and thus are similar to
such other CNS depressants as alcohol and barbituates.
The term "major tranquilizer" was formerly
applied to drugs used to treat severe mental illnesses, such as schizophrenia.
However, these drugs are now more commonly called neuroleptics; their action
specifically relieves the symptoms of mental illness, and they are rarely
misused for other purposes. This paper therefore deals with the anti-anxiety
agents, or anxiolytics (formerly called "minor" tranquilizers).
Anti-anxiety agents share many
similiarities with barbituates; both are classified as sedative/hypnotics.
These newer agents were introduced under the term "tranquilizer"
because, it was claimed, they provided a calming effect without sleepiness.
Today, tranquilizers have largely replaced barbiturates in the treatment of
both anxiety and insomnia because they are safer and more effective. The degree
of sleepiness induced depends on the dosage. Tranquilizers are also used as sedatives
before some surgical and medical procedures, and they are sometimes used
medically during alcohol withdrawal.
Although tranquilizers do not exhibit the serious
dependence characteristics of barbiturates, they nevertheless can produce
tolerance and dependence. They may also be misused and abused.
The first drug to be labelled a tranquilizer was
meprobamate - under the trade name Miltown - in 1954. Today, however, the most
popular anti-anxiety agents are the benzodiazepines (e.g. Valium, Halcion, and
Ativan).
The first benzodiazepine developed was
chlordiazepoxide, which is sold under such trade names as Librium and
Novopoxide. The next was diazepam; it is marketed, among other brand names, as
Valium, E-Pam, and Vivol. In the early 1970s diazepam was the most widely
prescribed drug in
Now Halcion and Ativan - drugs from the same family as
diazepam but eliminated more rapidly from the body - account for most
benzodiazepine prescriptions. Some are prescribed as anti-anxiety drugs (e.g.
Valium, Librium); others are recommended as sleeping medications (e.g. Dalmane,
Somnol, Novoflupam, and Halcion).
Effects
The effects of any drug depend on several
factors:
With tranquilizers, a therapeutic
dose (i.e. what is medically prescribed) relieves anxiety and may, in some
people, induce a loss of inhibition and a feeling of well-being. Responses
vary, however. Some people report lethargy, drowsiness, or dizziness.
Tranquilizers, though, have very few side effects.
As the dose of a tranquilizer is increased, so is
sedation and impairment of mental acuity and physical coordination. Lower doses
are recommended for older people or for those with certain chronic diseases,
since their bodies tend to metabolize these drugs more slowly.
Studies show that anti-anxiety agents, even at the
usually recommended and prescribed doses, may disrupt the user's ability to
perform certain physical, intellectual, and perceptual functions. For these
reasons, users should not operate a motor vehicle or engage in tasks calling
for concentration and coordination. Such activities are particularly hazardous
if tranquilizers are used together with alcohol and/or barbiturates (i.e. other
sedative/hypnotics) or antihistamines (in cold, cough, and allergy remedies).
These effects occur early in therapy, however, and wane over time with
increased tolerance (when more of the drug is needed to produce the same
effect).
Because some tranquilizers (such as diazepam) are
metabolized quite slowly, residue can accumulate in body tissues with long-
term use and can heighten such effects as lethargy and sluggishness.
Toxic Effects
Tranquilizer overdose, particularly with
benzodiazepines, has become increasingly common since the 1960s. While these
drugs are usually safe even when an overdose is taken (death rarely results
from benzodiazepine use alone), they can be fatal in combination with alcohol
and other drugs that depress the central nervous system.
In
Tolerance and Dependence
Because tolerance to the mood-altering effects
of tranquilizers can develop with regular use, higher daily doses become
necessary to maintain the desired effects. Tolerance may occur even at
prescribed doses.
Chronic users may become both psychologically and
physically dependent on tranquilizers.
Psychological dependence exists when a drug is so central to a person's
thoughts, emotions, and activities that the need to continue its use becomes a
craving or compulsion.
With chronic use, especially at higher doses, physical
dependence can also occur. The user's body has adapted to the presence of
the drug and suffers withdrawal symptoms when use is stopped. The frequency and
severity of the withdrawal syndrome depends on the dose, duration of use, and
whether use is stopped abruptly or tapered off. Symptoms range in intensity
from progressive anxiety, restlessness, insomnia, and irritability in mild
cases to delirium and convulsions in severe cases.
Dependence may also occur
following long-term therapeutic use, but withdrawal symptoms in such cases are
mild. Patients complain of gastrointestinal problems, loss of appetite, sleep
disturbances, sweating, trembling, weakness, anxiety, and changes in perception
(e.g. increased sensitivity to light, sound, and smells).
Risk of dependency
increases if tranquilizers are taken regularly for more than a few months,
although problems have been reported within shorter periods. The onset and severity of withdrawal differ between
the benzodiazepines that are rapidly eliminated from the body (e.g. Halcion)
and those that are slowly eliminated (e.g. Valium). In the former case,
symptoms appear within a few hours after stopping the drug and may be more
severe. In the latter case, symptoms usually take a few days to appear.
Tranquilizers and Pregnancy
If a woman uses tranquilizers regularly, the drug can
affect the baby for up to 10 days after birth. Babies may exhibit the
withdrawal symptoms common to such other depressant drugs as alcohol and
barbituates. These symptoms include feeding difficulties, disturbed sleep,
sweating, irritability, and fever. Symptoms will be more severe if the doses
the mother took are higher.
Administration of diazepam during labor has been linked
to decreased responsiveness and respiratory problems in some newborns.
Lateral and third ventricle enlargement: associated
sulcal enlargement; cortical atrophy |
|
|
|
"Loss of brain volume associated with
schizophrenia is clearly shown by magnetic resonance imaging (MRI) scans
comparing the size of ventricles (butterfly shaped, fluid-filled spaces in
the midbrain) of identical twins, one of whom has schizophrenia (right). The
ventricles of the twin with schizophrenia are larger. This suggests
structural brain changes associated with the illness."- Source:
Daniel Weinberger, MD, NIMH Clinical Brain Disorders Branch--used with
permission |
Decreased thalamic and prefrontal cortex neuronal
metabolism & altered brain metabolism (PET) |
|
"NIMH scientist shows PET scans from a study of
identical (monozygotic) twins, who are discordant for schizophrenia (only one
has the disorder) demonstrating that individuals with schizophrenia have
reduced brain activity in the frontal lobes (top of scan)."--http://www.nimh.nih.gov/hotsci/scanschi.htm
used with permission |
Positron Emission Tomography (PET) "PET ( positron emission
tomography) is a brain imaging technique that uses a radioactive tracer to
show chemical activity of the brain. The PET scanner pinpoints the
destination of radioactively tagged glucose, oxygen, or drugs to reveal the
parts of the brain involved in performing an experimental task. PET allows us to look at brain functions by
measuring levels of energy - or activity - in specific areas of the brain.
PET scans generate pictures of the working brain, providing maps of emotions,
learning, vision, and memory. For example, patients may be injected with a
form of radioactive glucose. The glucose winds its way to the brain through
the bloodstream. Since glucose is normally the brain's fuel, the more active
a part of the brain is during the task, the more glucose it uses. An array of
radiation detectors in the scanner locates the radioactivity and sends the
data to a computer that produces two-dimensional color-coded images (brighter
colors indicate more activity) of where the brain is active. Identifying these
brain functions is key in developing new ways to
diagnose and treat schizophrenia and other mental disorders". Source:William Branson NIH Medical Arts |
Dopamine |
|
|
Antipsychotic
drugs-chemical classifications
Basic Antipsychotic Drug Pharmacology
1. discontinuation or antipsychotic drug dose reduction
2. eliminate centrally acting anticholinergic drugs
(anti-Parkinsonian drugs/tricyclic antidepressants)
3. in absence those adequate therapeutic response:
high-dose diazepam (30-40 milligrams per day)
Clinical
Indications for Antipsychotic Drugs
Antipsychotic Drug Classes: Potencies and Toxicities
Chemical Class |
Drug |
Potency |
Extrapyramidal Effects |
Sedation |
Alpha blockade:
hypotension |
Phenothiazine:
aliphatic |
chlorpromazine
(Thorazine) |
|
|
|
|
Phenothiazine:
piperazine |
fluphenazine
(Prolixin) |
|
|
|
|
Thioxanthene |
thiothixene (Navane) |
|
|
|
|
Butyrophenone |
haloperidol (Haldol) |
|
|
|
|
Dibenzodiazepine |
clozapine (Clozaril) |
|
|
|
|
Thienobenzodiazepine |
olanzapine (Zyprexa) |
|
|
|
|
--low
--very
high
adapted from Table 29-1: Potter, W. Z. and Hollister,
L.E.,Antipsychotic Agents and Lithium, in Basic and Clinical Pharmacology,
(Katzung, B. G., ed) Appleton-Lange, 1998, p 468. |
Some Antipsychotics
Drug Classifications |
||
Phenothiazines
|
Buterophenones
|
Dibenzodiazepine
|
1. effects on electrolyte/ion transport
2. neurotransmitter -- neurotransmitter release
modulation
3. influence on second messengers mediating transmitter
action
1. inhibiting conversion of IP2 to IP1
2. inhibiting conversion of IP to inositol
§ PIP2 : membrane
precursor to inositol triphosphate and diacylglycerol (IP3 and DAG)
1. choreoathetosis
2. motor hyperactivity
3. ataxia
4. dysarthria
5. aphasia
Lithium ions
Lithium salts (e.g., acetate,
carbonate) are effective in controlling the manic phase. The effect becomes
evident approx. 10 d after the start of therapy. The small therapeutic index
necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should
be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values
there is a risk of adverse effects. CNS symptoms include fine tremor,
ataxia or seizures. Inhibition of the renal actions of vasopressin leads to
polyuria and thirst. Thyroid function is impaired, with compensatory
development of (euthyroid) goiter. The mechanism of action of Li ions
remains to be fully elucidated. Chemically, lithium is the lightest of the
alkali metals, which include such biologically important elements as sodium and
potassium. Apart from interference with transmembrane cation fluxes (via ion
channels and pumps), a lithium effect of major significance appears to be
membrane depletion of phosphatidylinositol bisphosphates, the principal lipid
substrate used by various receptors in transmembrane signalling. Blockade of
this important signal transduction pathway leads to impaired ability of neurons
to respond to activation of membrane receptors for transmitters or other
chemical signals. Another site of action of lithium may be GTP-binding proteins
responsible for signal transduction initiated by formation of the agonist-
receptor complex. Rapid control of an acute attack of mania may require the use
of a neuroleptic.
1. http://www.youtube.com/watch?v=B61oprhnOuI&feature=related
2. http://www.youtube.com/watch?v=E4lI9UU2MZo&feature=channel
3. http://www.youtube.com/watch?v=d_-4QhO0hjY&feature=related
4. http://www.youtube.com/watch?v=xSUAsdBgh70&feature=related
5. http://www.youtube.com/watch?v=dBW9ZZGPQc8&feature=related
6. http://www.youtube.com/watch?v=u5dqemGc558&feature=related
7. http://www.youtube.com/watch?v=gk3mNOy__aM&feature=fvw
8. http://www.youtube.com/watch?v=ITkBMqwb-0Q&feature=related
9. http://www.youtube.com/watch?v=uaESK4ohM-I&feature=related
10. http://www.youtube.com/watch?v=KIjOZq_AUeE&feature=fvw
11. http://www.youtube.com/watch?v=AqJhWG1aSVQ&feature=channel
12. http://www.youtube.com/watch?v=rg3KgRXDB3k&feature=related
13. http://www.youtube.com/watch?v=cWx6RbBVTnA&feature=related
14. http://www.youtube.com/watch?v=ocSptPUBbuo&feature=related
15. http://www.youtube.com/watch?v=HryOhK4E7aU&feature=related
16. http://www.youtube.com/watch?v=pziYmeEM9Zg&feature=related