Drugs hypnotics, and anxiolytics

**counselor** Mon Oct 15, 2012 11:40 am

Drugs hypnotics, and anxiolytics

As for anxiety disorders, it is of psychiatric disorders characterized by anxiety of strong intensity and unjustified with debilitating consequences. These disorders are divided into several branches.

We distinguish:
• Generalized anxiety disorder (GAD) is characterized by excessive and unwarranted anxiety that manifests itself
constantly on a long time.
• Disorder panic attack (DAP), characterized by episodes of intense anxiety with tachycardia and tachypnea
• post-traumatic stress disorder, often occurs after a major trauma and is characterized by
generalized numbness, nightmares and overreactions
• Obsessive-compulsive disorder (OCD) is characterized by repetitive behaviors related to obsessions
subject
• Social phobias or simple, it is unjustified fear reactions to certain situations that occur in
persistently.

Ii sleep disorders other hand, consist in the difficulty of initiating and / or maintaining sleep, or the feeling of having a unrefreshing sleep.

BENZODIAZEPINES (BDZ)

Benzodiazepines are now considered drugs of first choice for acute anxiety.

DRUGS THAT BELONG TO BDZ:
Psycholeptics-anxiety (where psicolettico means that "depressed, reduces mental activity"):
Alprazolam (Xanax);
Diazepam (Valium);
Chlordiazepoxide (Librium);
Clonazepam (Rivotril), this is also used as an antiepileptic drug in absences.
Bromazepam (Lexothan, Lexil, Lexotanil);
Lorazepam (Ativan);
Delorazepam (Laroxil);
Clotiazepam (Rizen).

Psycholeptics-hypnotics:
Lormetazepam (Minias);
Fluitrazepam (Rohypnol)
Triazolam (Halcion and Songar);
Midazolam.

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PHARMACODYNAMICS

Mechanism of action:
The main target for the action of benzodiazepines is the GABA receptor A. The GABA B receptors do not seem affected by benzodiazepines.
The neurotransmitter GABA is the main inhibitory pathways in the CNS.

Benzodiazepines allosterically modulate the GABA A receptor, requiring the involvement of GABA in the final mediate their effects. This explains why the depressant effects of benzodiazepines have a plateau of moderate intensity (as opposed to barbiturates).
Benzodiazepines increase the binding of GABA and increase the frequency of opening of chloride channels.

Sedative effect
A low-dose benzodiazepines reduce the hyperactivity of the subject and will moderate excitement.

Hypnotic effect (higher doses)
1) Decrease the latency of sleep.
2) Effect of varying the duration of stage 1 sleep (the sleep light)
3) All benzodiazepines increase the duration of phase 2 (Sleep overt, the duration of which accounts for approximately 50% of the sleep).
4) decreased stages 3 and 4 (slow wave sleep). The reduction of step 4 reduces nightmares and episodes of pavor nocturnus.
5) The reduced duration of REM sleep (characterized by rapid eye movements) in the early hours, but then increased REM cycles. Overall, it has modest reduction in REM sleep. Benzodiazepines give the patient the feeling that sleep was refreshing.
6) Decrease the number of awakenings during sleep. The total duration of sleep increases (up to three times).

Anxiolytic effect
Site of action for the anxiolytic effect is believed to be the limbic system (septum, amygdala, hippocampus).
Benzodiazepines have a ready anxiolytic effect from the first dose.

Anticonvulsant effect
Not abolish the abnormal discharge of epileptogenic foci, but suppress the spread of ictal activity.
Benzodiazepines are useful in treating status epilepticus. In this regard you can use intravenous diazepam
Clonazepam may be useful in the treatment of petit mal.

Muscle relaxant effect
Diazepam has a strong muscle relaxant action.
The GABA, liberated at the level of the spinal cord, goes to inhibit axonal endings of primary afferent fibers. It follows presynaptic inhibition of tonic reflexes miotassici
The diazepam, increasing the GABAergic action is useful in the treatment of patients with muscle spasticity induced by spinal cord injuries or cerebral palsy. The main side effect is sedation.

Cognitive functions
At high doses, benzodiazepines produce anterograde amnesia

Respiratory effects
At doses of hypnotic benzodiazepines are no respiratory effects. At doses depress slightly preanestetiche pulmonary ventilation and cause respiratory acidosis.
When administering other CNS depressants then severe respiratory depression may occur.

Effects on the cardiovascular system
Hypnotic doses have modest cardiovascular effects. High doses decrease the blood pressure and increase heart rate.
Diazepam increases coronary flow perhaps by increasing the concentration of interstitial adenosine.

Gastrointestinal tract
The diazepam decreases the nocturnal gastric secretion in humans. Few data with other benzodiazepines.
They are useful in the treatment of gastrointestinal disorders related to anxiety.

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Abuse of benzodiazepines
Abuse of benzodiazepines may occur in different situations:
1) In the patient undergoing therapy for the treatment of insomnia or anxiety.
a) It can occur increasing the dose evening
b) Taking medicine even in the morning
2) Consumers of opiates benzodiazepines to enhance heroin "weak", or when they become tolerant to opiates.
3) Benzodiazepines short duration of action are taken from alcoholics to alleviate withdrawal symptoms from alcohol or to prevent "the smell of alcohol".

The drug can become an important part of the life of the consumer.
Abusers of benzodiazepines can assume hundreds of mg per day.

The number of documented cases of drug from benzodiazepines is low (especially in relation to their widespread use).
This may be due to the fact that in normal subjects benzodiazepines are not considered particularly "reinforcing".
Can be even more easily soluble drug dependence benzodiazepines such as diazepam.

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Tolerance and dependence
You may develop tolerance to the sedative-hypnotic and anticonvulsant. The tolerance is mostly nature of pharmacodynamics, probilmente linked to altered expression of subunits of the GABA-A receptor.

Long-term treatment with high doses carry the risk of dependence, which is a modification of the physiological state that requires continued administration to prevent withdrawal symptoms.
The withdrawal syndrome is manifested by:
• Insomnia, anxiety and irritability
• tachycardia and tachypnea
• photophobia and increased temperature
• tremors and convulsions
The syndrome appears later for benzodiazepines long duration of action.

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Drug Interactions
Concomitant ingestion of alcohol amplifies the depressant effects on the CNS, with the risk of respiratory and circulatory depression until coma.
Similar result occurs for concomitant administration of tricyclic antidepressants, antipsychotics, opioids, anticonvulsants.
The metabolism of benzodiazepines is reduced by estrogen, propranolol, cimetidine, and is accelerated by rifampicin (enzyme)

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PHARMACOKINETICS

Pharmacokinetics expresses the passage of the drug since it has taken until you delete it.

• For oral administration are absorbed almost completely. The peak plasma concentration is reached between 0.5 and 8 hours. [Triazolam (active dell'Halcion) = 1 now].
• The rectum is used in children with febrile seizures and causes effect in 3-4 min.
• After administration I.M. absorption rather slow, perhaps due to precipitation of the drug.
• Intravenous administration is used when it is necessary to have an immediate effect (status epilepticus)

At first, the distribution is based on circulation (brain and other organs richly perfused). Then redistribution in muscle tissue and fat. Well through the blood-brain barrier and the placenta. Pass into the milk.

Strong binding to plasma proteins (99% for diazepam).

Benzodiazepines are subject to significant metabolism by hepatic microsomal enzymes, particularly CYP3A4 and CYP2C19.
1) The benzodiazepines with an alkyl substituent in position 1 or 2 firstly undergo dealkylation. Dealkylated compounds are biologically active and are biotransformed slowly (half-life can be even longer than 20 hours!).
2) The next step is the hydroxylation of the methyl group position 3 or triazole ring for triazolam and alprazolam.
3) followed by conjugation with glucuronic acid and excretion.

So the effect of a compound benzodiazepine can take a very long time.
Benzodiazepines with shorter half-life triazolam and midazolam (half-life of 2-5 hours)

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TOXICITY '

Benzodiazepines are relatively safe drugs. Although an overdose usually does not cause severe respiratory depression or cardiovascular disease. Please note, however, the concomitant use of alcohol or other CNS depressants. Benzodiazepines cause:

• Increased reaction time. Impairment of mental function for residual effects after hypnotic doses (hangover)
• Anterograde amnesia, blurred vision, motor incoordination, ataxia at high doses
• Elderly daytime sedation increases the risk of falls and fractures
• Heavy interaction with ethanol and other CNS depressants. Together with other CNS depressants can be observed severe respiratory depression. Benzodiazepines alone do not cause severe respiratory depression
• Nausea, vomiting, epigastric distress, and diarrhea.
• abuse and drug dependence. Physical dependence with the consequent problem of the withdrawal syndrome after cessation of dosing.

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THERAPEUTIC INDICATIONS

1. Anxiolytic therapy
- Benzodiazepines are considered drugs of choice for acute or subchronic treatments (2-4 weeks). Treatment you can have more protracted development of tolerance.
- For this use, it takes a long-acting compounds (chlordiazepoxide, diazepam, flurazepam, clobazam, bromazepam)
- In the anxiety disorders characterized by panic and phobia are better antidepressants
- The latter are used for treatments anxiolytics more protracted

2. Treatment of insomnia
- In the presence of a specific cause of insomnia using specific medications (analgesics, antidepressants, antipsychotics) or psychotherapy.
- Benzodiazepines are hypnotic of choice for: perceived quality of sleep, good therapeutic index, limited likelihood of abuse.
- Insomnia in the short term (due to causes momentary): start with small doses of benzodiazepines, stop treatment after 1 or 2 nights of sleep acceptable. Not prolong treatment for more than 3 weeks.
- Insomnia long-term benzodiazepines only in the early stages of treatment and the frequency of a night treatment alternating with 2 nights without hypnosis.
- Do not prolong the treatment for 3-6 months. Psychotherapy as an alternative.
- The triazolam be recommended if there is a long time of sleep latency, but do not occur awakenings. Benzodiazepines such as lorazepam temazepan or if the main problem are the awakenings.
- If anxiety is the root cause of insomnia may be more useful a benzodiazepine with a long half-life

3. Epilepsy and seizures
They are mainly used in status epilepticus (diazepam), in convulsions associated with alcohol withdrawal syndrome and absence seizures (clonazepam).

4. Neurological Disorders
The muscle relaxant effect is exploited for the treatment of muscle spasticity associated with neurological disorders.

5. Use the "anesthetic"
Benzodiazepines do not produce a good general anesthesia remains the conscience and has sufficient muscle relaxation even at high doses.
For their sedative effect, are useful in the perioperative period and interventions in low-invasive (bronchoscopy, gastroscopy)
Damage anterograde amnesia, which creates the illusion that there was anesthesia.
The benzodiazepine most used for this purpose is the midazolam (half-life of 2-3 hours)

Flumazenil
In case of poisoning by benzodiazepines may be used with flumazenil, a competitive antagonist of the receptor for benzodiazepines.
Its use is indicated for intravenous administration. It is not active against overdose of barbiturates or tricyclic antidepressants.
Flumazenil also blocks the effect of beta-carbolines, inverse agonists capable of binding with high affinity benzodiazepine receptor sites, evoking action anxiety.

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Non-benzodiazepine anxiolytic

These unlike the BDZ not damage tolerance.

There apartengono drugs such as:
-Buspirone (Buspar).

-SSRI antidepressants:
Fluoxetine (Diesan, Deprexen, Flotina, Clexiclor, and Cloriflor Azur);
Paroxetine (Daparox, Dopraxin, Eutimil)
Sertraline (Zoloft, Tatig).

-SNRI antidepressants:
Venlafaxine (Efexor, Faxine)

ANTIDEPRESSANTS

• For long-term treatments are preferred antidepressant drugs because they do not damage tolerance or dependence.
• Antidepressants are considered drugs of choice for generalized anxiety disorder (GAD) and panic attack disorder (DAP)
• Among the most commonly used antidepressants have: SSRIs (such as paroxetine - pa of Sereupin, Seroxat, Eutimil and Daparox - and sertraline - pa of Zoloft) and SNRIs (eg venlafaxine - pa dell'Efexor or Faxine).
• A benzodiazepine may be associated with antidepressant in the first days of therapy, since the action dell'antidepressivo manifests itself after a few weeks.

BUSPIRONE (pa of the Buspar)
It 'sa azapirone, originally developed as antipsychotic agent.
• It has no affinity for benzodiazepine receptors
• E 'partial agonist for the 5-HT1A receptors
• Compared to benzodiazepines causes less amnesia and impairment of motor performance.
• Do not potentiate the effect of alcohol
• No anticonvulsant effect
• It may be of some interest for long-term treatment. Its effect appears after 3-6 weeks
• It is useful in case of panic attacks.

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Non-benzodiazepine hypnotics

Even these as the previous ones, unlike the BDZ not cause tolerance.

Belong drugs such as:
Zopiclone (Imovane) by the duration of action from 3 to 6 hours;
Zolpidem (Stilnox, Niotal, Nottem) by the duration of action of 2 hours;
Zaleplon (Sonata, Zerene) by the duration of action of 1 hour.

Zopiclone (active ingredient of a drug called Imovane)

• Has GABAergic mechanism of action
• It has a short half-life (3-6 hours) that does not give residual effects upon awakening.
• Its main side effect is to induce a metallic taste.

Zolpidem (Stilnox the pa, and Nottem Niotal)

• It 'an imidazopyridine.
• It binds to sites for benzodiazepines (especially subunit beta-1) and has similar effects on sleep.
• It differs from benzodiazepines because it has no effect anticonvulsant and muscle relaxant
• Has little tendency to produce tolerance
• Induces addictive as benzodiazepines
• It has the advantage of giving infrequently residual sedation or amnesia.
• Its half-life is rather short (2 hours).

Zaleplon (Sonata and Zerene of pa)

E 'a pirazolopirimidina
Binds to sites for benzodiazepines (especially subunit  1) and has similar effects on sleep.
Has half-life of about 1 hour, for which does not give residual effects on awakening. And 'the lower half-life hypnotic.
Has little tendency to produce tolerance

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Barbiturates

Are derived from barbituric acid (malonylurea). And some of them, as well as anticonvulsant and antiepileptic, are used as anxiolytics and hypnotics. For example: Phenobarbital (Gardenale).

PHARMACODYNAMICS

Depress the activity of all excitable tissues.
The CNS is sensitive to their action.
Barbiturates are capable of producing all levels of CNS depression to general anesthesia.

Antianxiety effect
Occurs at doses 2-8 times lower than those hypnotic. Barbiturates have been used as anxiolytics, but with results lower than those of benziodiazepine.

Euphoric effect
When it reaches the maximum intensity is comparable to that of morphine.

Effect iperalgesizzante
The perception of pain is never changed until loss of consciousness. Indeed, in small doses are iperalgesici.

Hypnotic effect
a) decreases sleep latency and number of awakenings
b) It prolongs the duration of phase 2.
c) are abbreviated stages 3 and 4.
d) markedly decreases the activity REM

With barbiturates, sleep is not evaluated as a restaurateur.
It establishes tolerance to the hypnotic effect (after 2 weeks is reduced by 50%).

General anesthetic effect
Using thiopental (Penthotal) for its brevity of action.
Intravenous (not injected outside the vein to the risk of necrosis).
The effect istaura immediately and lasts only 20-30 min for redistribution in extracerebral tissues.

Anticonvulsant effect
The anticonvulsant activity maximum occurs with a phenolic group in the molecule, as in the phenobarbital.
This drug exerts anticonvulsant at doses lower than those hypnotic.

A toxic dose barbiturates have depressing effects on skeletal muscle, cardiac and smooth.

MECHANISM OF ACTION
• Barbiturates act on GABA-A
• Benzodiazepines are not moved from their binding sites by barbiturates (separate sites).
• Barbiturates prolong the activation of the channel for the Cl-.
• At high doses barbiturates may increase the conductance for ions Cl-even in the absence of GABA.

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PHARMACOKINETICS
• The phenobarbital is administered orally.
• When using the anesthetic pentobarbital intravenously.
• Avoid intramuscular (necrosis).
• For fat-soluble barbiturates has maximum uptake in the CNS in only 30 s.
• Within 30 minutes the drug is redistributed to other tissues.
• Barbiturates very little soluble are eliminated in the urine, but especially for hepatic metabolism.
• Barbiturates are more water soluble to a greater extent eliminated in the urine. In the case of phenobarbital approximately 25% is excreted in the urine.

ACUTE INTOXICATION
May be due to:
-Deliberate suicide attempt
Automatism-pharmacological
-Accidental poisoning

In intoxication serious:
- Comatose state
- Pupils first miotic (but which respond to light) then dilated paralysis by hypoxia.
- Breath slow or fast but shallow. Cheyne-Stokes rhythm.
- The pressiona blood decreases markedly
-Pulmonary complications (edema, pneumonia).

Treatment of intoxication
-Gastric lavage within 24 hours + saline purgative
-Prevent further heat loss
Check-breathing
-Perform mechanical ventilation if necessary.
-Correct volume and blood pressure support with dopamine in the shock
-Accelerate the renal elimination of the barbiturate alkalinizing the urine. If necessary hemodialysis.

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ABUSE AND ADDICTION
• Abuse by opiate users and alcoholics by
• With barbiturates euphoric effects much more pronounced than with benzodiazepines.
• Increased risk of drug than with benzodiazepines.
• The withdrawal syndrome is similar to that described for benzodiazepines: insomnia, anxiety, increased rebound of REM sleep, tremors and weakness. Severe cases can cause even tonic-clonic convulsive fits. To prevent the withdrawal syndrome, one operates gradual weaning (such as 0.1 g per day of pentobarbital less).

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THERAPEUTIC USES
I'm currently using:
pentobarbital as general anesthetic
Phenobarbital for:
1) tonic-clonic generalized
2) partial access.

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