Hipnotice + Antiepileptice

8/16/2019 Hipnotice + Antiepileptice

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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. owever, a few abusers will in!ect

their drugs intravenously. The in!ection 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 thic"er than the heroin solution. The in!ection

sites on the s"in 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

!udgment 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.

$epressants vary in the amount of time it ta"es the user to feel the effects and also

the amount of time the effects are felt. %ome depressants act very &uic"ly, and begin

to affect their user within seconds. 'thers act more slowly, sometimes ta"ing one#half

hour or more to begin to exert an influence. The &uic"#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.

'verdoses 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 s"in may feel cold and clammy, and death may

result from respiratory failure.

Neuroleptic: synonym for antipsychotic drug; originally indicated drug ith

antipsychotic efficacy !ut ith neurologic "e#trapyramidal motor$ side effectsTypical neuroleptic( older agents fitting this description

Atypical neuroleptic( newer agents( antipsychotic efficacy with reduced or no

neurologic side effects

%he neuroleptic drugs "also called antipsychotic drugs, or ma&or

tranquilizers$ are used primarily to treat schi)ophrenia, but they are also effective in

other psychotic states, such as manic states with psychotic symptoms such as


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grandiosity or paranoia and hallucinations, and delirium. All currently available

antipsychotic drugs that alleviate symptoms of schi)ophrenia 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 bloc"ing of

dopamine receptors. These drugs vary in potency. /or example, chlorproma)ine is a

low#potency drug, and fluphena)ine is a high#potency agent. 0o one drug is clinically

more effective than another. 1n 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 uni&ue activity to bloc"ade of both serotonin and dopamine -and,

perhaps, other receptors. Current antipsychotic therapy commonly employs the use

of the atypical agents to minimi)e the ris" of debilitating movement disorders

associated with the typical drugs that act primarily at the $2 dopamine recep

tor. Allof the atypical antipsychotics exhibit an efficacy that is e&uivalent to, or occasionally

exceeds, that of the typical neuroleptic agents. owever, 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. 0euroleptic 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 schi)ophrenia to

function in a supportive environment.

'ypnotic agents. (ntiepileptic drugs

$uring sleep, the brain generates a patterned rhythmic activity that can be monitored

by means of the electroencephalogram -334. 1nternal sleep cycles recur 5 to 6 times

per night, each cycle being interrupted by a ) apid *ye +ovement -73M sleep

phase "($. The 73M stage is characteri)ed by 334 activity similar to that seen in the

wa"ing state, rapid eye movements, vivid dreams, and occasional twitches of

individual muscle groups against a bac"ground of generali)ed atonia of s"eletal

musculature. 0ormally, the 73M stage is entered only after a preceding non#73M

cycle. /re&uent interruption of sleep will, therefore, decrease the 73M portion. %hortening of 73M sleep -normally approx. 268 of total sleep duration

results in increased irritability and restlessness during the daytime. With undisturbed

night rest, 73M deficits are compensated by increased 73M sleep on subse&uent

nights "$.


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ypnotics fall into different categories, including the !enzodiazepines -e.g.,

tria)olam, tema)epam, clotia)epam, nitra)epam, !ar!iturates -e.g., hexobarbital,

pentobarbital, chloral hydrate, and 9#antihistamines with sedative activity.

:en)odia)epines 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 73M stages "$.


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With repeated ingestion of a hypnotic on several successive days, the proportion of

time spent in 73M vs. non#73M sleep returns to normal despite continued drug

inta"e. Withdrawal of the hypnotic drug results in 73M rebound, which tapers off


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only over many days "$. %ince 73M stages are associated with vivid dreaming, sleep

with excessively long 73M 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.

$epending on their blood levels, both ben)odia)epines and barbiturates

produce calming and sedative effects, the former group also being an#iolytic. At

higher dosage, both groups promote the onset of sleep or induce it "C$.

;nli"e barbiturates, !enzodiazepine derivatives administered orally lac" a generalanesthetic 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, ben)odia)epines possess a therapeutic

margin considerably wider than that of barbiturates. -olpidem -an imida)opyridine

and zopiclone -a cyclopyrrolone are hypnotics that, despite their different chemical

structure, possess agonist activity at the ben)odia)epine receptor.


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$ue to their narrower margin of safety -ris" of misuse for suicide and their potential

to produce physical dependence, !ar!iturates are no longer or only rarely used as

hypnotics. $ependence on them has all the characteristics of an addiction. :ecause of

rapidly developing tolerance, choral hydrate is suitable only for short#term

use.(ntihistamines 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/a0e Cycle and 'ypnotics

The physiological mechanisms regulating the sleep#wa"e rhythm are not completely

"nown. There is evidence that histaminergic, cholinergic, glutamatergic, and

adrenergic neurons are more active during wa"ing than during the 073M sleep stage.

=ia their ascending thalamopetal pro!ections, these neurons excite thalamocortical

pathways and inhibit 4A:A#ergic neurons. $uring sleep, input from the brain stemdecreases, giving rise to diminished thalamocortical activity and disinhibition of the

4A:A neurons "($.

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 pea" before midnight "1$.

%reatment of sleep distur!ances. >harmacotherapeutic 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 "2$, 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 wa"ing periods. $epending on the

type of insomnia, ben)odia)epines with short or intermediate duration of action areindicated,e.g., tria)olam and broti)olam -t9*2 ? 5@ h< lormeta)epam or tema)epam

-t9*2 ? 9B@96 h. These drugs shorten the latency of falling asleep, lengthen total

sleep duration, and reduce the fre&uency of nocturnal awa"enings. They act by

augmenting inhibitory activity. 3ven with the longer#acting ben)odia)epines, the

patient awa"es after about @ h of sleep, because in the morning excitatory activity

exceeds the sum of physiological and pharmacological inhibition "3$.The drug effect


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may, however, become unmas"ed 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 fre&uent interruption of

nocturnal sleep "C$.


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;se of a hypnotic drug should not be extended beyond 5 w", because tolerance may

develop. The ris" of a rebound decrease in sleep propensity after drug withdrawal

may be avoided by tapering off the dose over 2 to D w". With any hypnotic, the ris" of

suicidal overdosage cannot be ignored. %ince ben)odia)epine intoxication may

become life#threatening only when other central nervous depressants

-ethanol are ta"en simultaneously and can, moreover, be treated with specific

ben)odia)epine antagonists, the ben)odia)epines should be given preference as sleep

remedies over the all but obsolete barbiturates.

enzodiazepines

:en)odia)epines modify affective responses to sensory perceptions< specifically, they

render a sub!ect indifferent towards anxiogenic stimuli, i.e., an#iolytic action.

/urthermore, ben)odia)epines exert sedating, anticonvulsant, and muscle4

rela#ant -myotonolytic effects. All these actions result from augmenting the activity

of inhi!itory neurons and are mediated by specific !enzodiazepine receptors thatform an integral part of the 4A:AA receptor# chloride channel complex. The

inhibitory transmitter 4A:A acts to open the membrane chloride channels.

1ncreased chloride conductance of the neuronal membrane effectively shortcircuits

responses to depolari)ing inputs. :en)odia)epine receptor agonists increase the

affinity of 4A:A to its receptor. At a given concentration of 4A:A, binding to the

receptors will, therefore, be increased, resulting in an augmented response.

3xcitability of the neurons is diminished. Therapeutic

indications for ben)odia)epines include an#iety states associated with neurotic,

pho!ic, and depressive disorders, or myocardial infarction-decrease in cardiac

stimulation

due to anxiety< insomnia; preanesthetic -preoperative medication< epileptic

seizures; and hypertonia of s"eletal musculature -spasticity, rigidity. %ince 4A:A#

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 ben)odia)epines, calculated with

reference to the toxic dose producing respiratory depression, is greater than 9BB and

thus exceeds that of barbiturates and other sedative#hypnotics by more than tenfold.:en)odia)epine intoxication can be treated with a specific antidote -see below. %ince

ben)odia)epines depress responsivity to external stimuli, automotive driving s"ills

and other tas"s re&uiring precise sensorimotor coordination will be

impaired. Triazolam -t9*2 of elimination [email protected] h is especially li"ely 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


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hostility, hallucinations, and their increased fre&uency in the elderly, has led to

curtailed or suspended use of tria)olam in some countries -;E. Although

ben)odia)epines are well tolerated, the possibility of personality changes

-nonchalance, paradoxical excitement and the ris" of physical dependence with

chronic use must not be overloo"ed. Conceivably, ben)odia)epine dependence results

from a "ind of habituation, the functional counterparts of which become manifest

during abstinence as restlessness and anxiety< even sei)ures may occur. These

symptoms reinforce chronic ingestion of ben)odia)epines. enzodiazepine

antagonists, such as fluma)enil, possess affinity for ben)odia)epine receptors, but

they lac" intrinsic activity. /luma)enil is an effective antidote in the treatment of

ben)odia)epine overdosage or can be used postoperatively to arouse patients sedated

with a ben)odia)epine. Whereas ben)odia)epines possessing agonist activity

indirectly augment chloride permeability, inverse agonists exert an opposite action.

These substances give rise to pronounced restlessness, excitement, anxiety, andconvulsive sei)ures. There is, as yet, no therapeutic indication for their

use.5harmaco0inetics of enzodiazepines All ben)odia)epines 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

pharmaco"inetic properties. 1ndividual ben)odia)epines remain in the body for very

different lengths of time and are chiefly eliminated through biotransformation.

1nactivation may entail a single chemical reaction or several steps -e.g., dia)epam

before an inactive metabolite suitable for renal elimination is formed. %ince 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.

:iotransformation begins either at substituents on the dia)epine ring -diazepam: 0#

deal"ylation at position 9< midazolam: hydroxylation of the methyl group on the

imida)ole ring or at the dia)epine ring itself. ydroxylated mida)olam is &uic"ly

eliminated following glucuronidation -t9*2 ? 2 h.

0#demethyldia)epam -norda)epam is biologically active and undergoes

hydroxylation at position D on the dia)epine ring. The hydroxylated product-oxa)epam again is pharmacologically active. :y virtue of their long half#lives,

dia)epam -t9*2 ? D2 h and, still more so, its metabolite, norda)epam -t9*2 6B@FB h,

are eliminated slowly and accumulate during repeated inta"e. 'xa)epam undergoes

con!ugation to glucuronic acid via its hydroxyl group -t9*2 G h and renal

excretion "($. The range of elimination half#lives for different ben)odia)epines or

their active metabolites is represented by the shaded areas "$.


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%ubstances 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 . %ubstances 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.

Mida)olam en!oys use by the i.v. route in preanesthetic medication and anesthetic

combination regimens. enzodiazepine 6ependence >rolonged regular use of

ben)odia)epines can lead to physical dependence. With the long#acting substances

mar"eted 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 t9*2, ranging from mild to moderate -restlessness, irritability, sensitivity to

sound and light, insomnia,and tremulousness to dramatic -depression, panic,

delirium, grand mal sei)ures. %ome of these symptoms pose diagnostic difficulties,

being indistinguishable from the ones originally treated. Administration of a ben)odia)epine antagonist would abruptly provo"e abstinence signs. There are

indications that substances with intermediate elimination half#lives are most

fre&uently abused -violet area in .

Clozapine is a prototype Hbroad#spectrumH antagonist. 1ts binding profile is &uite

different from other anti#psychotics both within and outside the dopaminergic system.

1t has relatively low affinity for $2 receptors in the striatum, while its in vitro affinity

for the $5 receptors is approximately ten times greater than that for $2 receptors, and

it has also been shown to bind to the $9, $D and $6 receptors. %ince $5 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 clo)apine in alleviating the symptoms of

schi)ophrenia without causing extra#pyramidal side#effects. Clo)apine has been

recognised to show significant activity at a broad range of receptors outside the $A

system. 'f particular interest is its high affinity for 6#T receptors, including 6#T2,

6#TD, 6#T and 6#TI subtypes. Clo)apine has high affinities for muscarinic A9

and A2 receptors, while it also has significant effects on 4A:A#ergic and

glutamatergic mechanisms.

5harmaco0inetics and +eta!olismAfter oral administration the drug is rapidly absorbed. There is extensive first#pass

metabolism and only 2I#6B8 of the dose reaches the systemic circulation unchanged.

1ts plasma concentration has been observed to vary from patient to patient. =arious

individual factors may vary response such as smo"ing, hepatic metabolism, gastric

absorption, age and, possibly, gender. Clo)apine is rapidly distributed. 1t crosses the

blood#brain barrier and is distributed in breast mil". 1t is F68 bound to plasma


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proteins. %teady#state plasma concentration is reached after I#9B days. The onset of

the anti#psychotic effect can ta"e several wee"s, but maximum effect may re&uire

several months. 1n treatment#resistant schi)ophrenia, patients have been reported to

continue to improve for at least two years after the start of clo)apine treatment.

Clo)apine metabolises into various metabolites, out of which only norclo)apine -a

desmethyl metabolite is pharmacologically active. The other metabolites do not

appear to have clinically significant activity. 1ts plasma concentration declines in the

biphasic manner, typical of oral anti#psychotics, and its mean elimination half#life

ranges from to DD hours. About 6B8 of a dose is excreted in urine and DB8 in the

faeces.

Cautions and Contra4indications

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. Clo)apine is

contra#indicated in patients with active liver disease, progressive liver disease and

hepatic failure. 'ther contra#indications include severe C0% depression or comatose

state, severe renal and cardiac disease, uncontrolled epilepsy, circulatory collapse,

alcoholic*toxic psychosis and previous hypersensitivity to clo)apine.

The most serious of clo)apineHs side#effects is agranulocytosis. 'ther important

side#effects include postural hypotension and tachycardia, sedation, sei)ures, weight

gain and rebound psychosis.

Clo)apine can also cause(

• 0ausea, vomiting and constipation.

• 3levation of liver en)ymes -fre&uency up to 9B8.

• ypersalivation -fre&uency 92#5B8.

• Confusion or delirium.

• 1ncontinence fre&uency*urgency, hesitancy, urinary retention, or impotence

-8.

• :enign hyperthermia -6#968.

1solated reports have been documented of clo)apine#associated emergence ofobsessive compulsive symptomsJ5,5IK , priapismJ5,5FK , allergic complicationsJ6B,69K .

pancreatitisJ62K , toxic hepatitisJ6DK , elevation in creatinine "inase levelsJ65K and diabetes#

li"e symptomsJ66,6K .

There have also been a handful of papers and case reports lin"ing clo)apine with

raised triglyceride levels. 4haeli and $ufresneJ6IK found that elevated serum

triglycerides in four patients resolved when they were switched to risperidone. 1n two


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of these patients clo)apine was re#introduced and again serum triglycerides increased.

They called for serum triglyceride levels to be monitored in clo)apine patients with

additional cardiac ris" factors. $ursun et al.J6K loo"ed at cholesterol and related lipids

in eight patients on clo)apine treatment over 92 wee"s. %erum triglyceride levels were

found to increase, but not cholesterol levels.

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