Transcript Neuroleptics. Anxiolytics

Kharkiv National Medical University
Department of Pharmacology and Medical Prescription
Assistant, PhD. Gordiychuk Daria
Psychotropic agents.
PLAN of LECTURE:
 1.
Neuroleptics.
 2. Anxyolitics.
 3. Lithium salts.
 4. Sedatives.
Introduction

The term psychosis refers to a variety of mental
disorders characterized by one or more of the
following symptoms:
1)
2)
3)
4)
5)
6)
Diminished and distorted capacity to process
information and draw logical conclusions;
Hallucinations, usually auditory or visual, but
sometimes tactile or olfactory;
Delusions (false believes);
Incoherence or marked loosening of
associations;
Catatonic or disorganized behavior;
Aggression or violence;
PSYCHOTROPIC DRUGS
Drugs with depressive type of action
1.
2.
3.
4.
Neuroleptics (antipsychotics)
Tranquilizers (anxiolytics)
Sedative drugs
Normotymics (tymoleptics, tymoanaleptics)
Drugs with stimulative action
1.
2.
3.
4.
Antidepressants
Psychomotor stimulants
Nootropic drugs
Drugs which increase general tone (adaptogens)
Psychotomimetics (psychodysleptics)
1.
2.
LSD
Cannabis sativa L.
Introduction cont.




The psychotic disorders include:
SCHIZOPHRENIA;
the manic phase of BIPOLAR (manic-depressive)
ILLNESS;
acute idiopathic PSYCHOTIC ILLNESSES;
other conditions marked by severe agitation.
Nature of Psychosis &
Schizophrenia

SCHIZOPHRENIA is a particular type of
psychosis characterized mainly by a clear
sensorium but a marked thinking disturbance.

Because it affects young people, is often chronic
and is usually highly disabling.

There is a strong hereditary factor in its
aetiology, and evidence suggestive of a
fundamental biological disorder
(neurodevelopmental disorder).
Schizophrenia - symptoms
Positive Symptoms
Hallucinations
Delusions (bizarre, persecutory)
Disorganized Thought
Perception disturbances
Inappropriate emotions
FUNCTION
Cognition
New Learning
Memory
Negative Symptoms
Blunted emotions
Anhedonia
Lack of feeling
Mood Symptoms
Loss of
motivation
Social withdrawal
Insight
Demoralization

Positive/active symptoms include thought disturbances,
delusions, hallucinations.

Negative/passive symptoms include social withdrawal,
loss of drive, diminished affect, paucity of speech,
impaired personal hygiene.
Neurochemical theories of
psychosis


Came mainly from analyzing the effects of
antipsychotic and propsychotic drugs from
pharmacology rather than from neurochemistry;
The main neurochemical theories centre on
dopamine and glutamate, although other mediators,
particularly 5-HT, are also receiving attention.
Neurochemical theories cont.
I.


The Dopamine theory of schizophrenia
It is based on multiple lines of evidence
suggesting that excessive dopaminergic activity
underlies schizophrenia;
It is still highly relevant to understanding the
major dimensions of schizophrenia, such as
positive and negative symptoms, cognitive
impairment, and possibly depression.
Neurochemical theories cont.
I.
The Dopamine theory of schizophrenia

However, the dopamine hypothesis is far from a
complete
explanation
of
all
aspects
of
schizophrenia, especially the cognitive impairment.
The Serotonin Hypothesis of Schizophrenia
II.


The Serotonin theory of schizophrenia
It has been found that 5-HT2A-receptor blockade is
a key factor in the mechanism of action of the
main class of atypical antipsychotic drugs such
as clozapine and quetiapine;
5-HT2A-receptors modulate the release of
dopamine, norepinephrine, glutamate, GABA and
acetylcholine in the cortex, limbic region, and
striatum.
12
Neurochemical theories
III.
The Glutamate theory of schizophrenia

Glutamate is the major excitatory neurotransmitter
in the brain;
Phencyclidine and ketamine are noncompetitive
inhibitors of the N-methyl-D-aspartate (NMDA)
receptor can exacerbate both cognitive impairment
and psychosis in patients with schizophrenia;


Hypofunction of NMDA receptors, located on
GABAergic
interneurons
contributed
to
schizophrenia.
The effects of DA, 5-HT and NE on the brain functions
Antipsychotic Agents


Are able to reduce psychotic symptoms in a wide
variety of conditions, including schizophrenia, bipolar
disorder, psychotic depression, senile psychoses,
various organic psychoses, and drug-induced
psychoses.
They are also able to improve mood and reduce
anxiety and sleep disturbances, but they are not the
treatment of choice when these symptoms are the
primary disturbance in nonpsychotic patients!!!
Antipsychotic Agents


Their antipsychotic actions appear to reflect a
blockade at dopamine and/or serotonin
receptors;
Many of these agents also block cholinergic,
adrenergic, and histaminergic receptors. The
undesirable side effects of these agents are often
a result of actions at these other receptors.
Several important DA-ergic systems or
pathways are now recognized in the brain:
(1) The first pathway (the one most closely related
to behavior) is the mesocortical tract,
which projects from cell bodies near the
substantia nigra to the limbic system and neocortex.
(2) The second system (the nigrostriatal tract)
consists of neurons that project from the substantia
nigra to the caudate and putamen; it is involved in
the coordination of voluntary movement.
3) The third pathway (the tuberoinfundibular
tract) connects arcuate nuclei and periventricular
neurons to the hypothalamus and posterior pituitary.
!!!DA released by these neurons physiologically
inhibits prolactin secretion!!!
Five DA receptors have been described, consisting
of two separate families – the D1- and D2-like groups:
(1) The D1-receptor is coded by a gene on chromosome 5, increases cAMP by activation of adenylyl
cyclase, and is located mainly in the putamen,
nucleus accumbens, and olfactory tubercle.
The second member of this family is D5. It is coded
by a gene on chromosome 4, also increases cAMP,
and is found in the hippocampus and hypothalamus.
The therapeutic potency of the most
antipsychotic drugs correlates strongly
with their D2-affinity.
(2) The D2-receptor family includes D2, D3 and D4receptors. D2-receptors is coded on chromosome
11, decreases cAMP (by inhibition of adenylyl
cyclase), and inhibits calcium channels
but opens potassium channels. It is found both
pre- and postsynaptically on neurons in the caudateputamen, nucleus accumbens, and olfactory
tubercle. A second member of this family, the
D3-receptor, also coded by a gene on chromosome
11, is thought to decrease cAMP and is located
in the frontal cortex, medulla, and midbrain.
The D4-receptor also decreases cAMP.
Distribution and characteristics of DA
receptors in the central nervous system
Classification of neuroleptics
I.

TYPICAL NEUROLEPTICS
(D2-blockers)
1. Phenothiazines
With aliphatic side chain


Chlorpromazine
(Aminazinum)
Triflopromazine
With piperidine side chain

Thioridazine
With piperazine side chain


Trifluoperazine
(Triftazinum)
Fluphenazine decanoate
2. Butyrophenones
 Haloperidol
 Droperidol
 Trifluperidol
3. Thioxanthenes
 Chlorprothixene
 Thiothixene
 Flupenthixol
Others:


Pimozide
Loxapine
Classification of neuroleptics
(cont.)
II.
Atypical neuroleptics





Clozapine
Olanzapine
Remazopride
Risperidone
Ziprasidone
Mechanisms of action of
neuroleptics
Antipsychotic effect of TYPICAL neuroleptics is
realized via blockade of dopamine receptors,
mainly D2 receptors of the mesolimbic and
mesocortical pathways.
 Antipsychotic effect of ATYPICAL neuroleptics
is realized via blockade of serotoninergic (5HT2), relatively selective D4 receptors and
α1- adrenoceptors.

Pharmacodynamic of neuroleptics
1. CNS: In normal individuals antipsychotics produce
neuroleptic syndrome – indifference to surroundings,
deficiency of thought, psychomotor slowing, emotional
quieting, reduction in initiative.
In psychotic patients neuroleptics reduce
irrational behaviour, agitation and aggresiveness.
They control psychotic symptomatology. Disturbed
thought and behaviour are gradually normalized,
anxiety is relieved. Hyperactivity, hallucinations,
and delusions are suppressed.
NB!!! The psychosedative effect is produced immediately
while the antipsychotic effect takes a week to develop.
Tolerance develops only to the psychosedative effect.
Pharmacodynamic of neuroleptics cont.
The thermoregulatory centre is turned off,
rendering the patient poikilothermic (body temperature falls if surroundings are cold and the contrary).
The medullary, respiratory and other vital centres
are not affected, except of very high doses. It is very
difficult to produce coma with neuroleptics.
Antiemetic effect is exerted through the CTZ
( D-ergic activity). Almost all neuroleptics, except
thioridazine, have this effect. However, they are
ineffective in motion sickness.
Antipsychotic agents produce
a state of rigidity and immobility (catalepsy).
Pharmacodynamic of neuroleptics cont.
2. ANS: Neuroleptics have varying degrees of
α-adrenergic blocking activity and produce
hypotension (primarily postural). The hypotensive
effect is more marked after parenteral administration.
Anticholinergic property of neuroleptics is weak.
The phenothiazines have weak H1-antihistaminic and
anti-5-HT actions as well. Promethazine has strong
sedative, and H1-antihistaminic action.
3. Endocrine system: Neuroleptics consistently
increase prolactin release by blocking the inhibitory
action of DA on pituitary gland. This may result
in galactorrhea and gynecomastia. They reduce
gonadotrophins, ACTH, GH and ADH secretion.
Psychiatric INDICATIONS of neuroleptics
1.Schizophrenia is the primary
indication for neuroleptics.
Unfortunately, many patients
show little response.
2.Antipsychotics are also indicated for schizoaffective
disorders, which share characteristics of both
schizophrenia and affective disorders.
The psychotic aspects of this illness require treatment
with antipsychotic drugs, which may be used with other
drugs such as antidepressants, lithium, or valproates.
Whilst a typical antipsychotics should
provide adequate treatment of positive symptoms
including hallucinations and delusions in at least
60% of cases, patients are often left with
unresolved negative symptoms such as
apathy, flattening of affect, and alogia.
Evidence suggests that clozapine and the newer
atypicals have a significant advantage over typical
drugs against negative symptoms.
Psychiatric INDICATIONS of neuroleptics
The manic phase in bipolar affective disorder often
requires treatment with neuroleptics (chlorpromazine,
haloperidol), though lithium or valproic acid
supplemented with high-potency benzodiazepines
(e.g. lorazepam or clonazepam) may suffice
in milder cases.
!!! Recent controlled trials support the efficacy of
monotherapy with atypical antipsychotics in the
acute phase (up to 4 weeks) of mania, and
olanzapine has been approved for this indication !!!
Psychiatric INDICATIONS of neuroleptics
Nonmanic excited states may also be managed
by antipsychotics, often in combination with
benzodiazepines.
Other indications for the use of antipsychotics
include disturbed behavior in patients with
Alzheimer's disease, and psychotic depression.
Antipsychotics are not indicated for the treatment
of various withdrawal syndromes, e.g. opioid
withdrawal. In small doses antipsychotics have
been promoted (wrongly) for the relief of anxiety
associated with minor emotional disorders, but
the anxiolytic agents are preferred.
Nonpsychiatric indications
(1) Most older antipsychotics, with the exception of
thioridazine, have a strong ANTIEMETIC EFFECT.
This action is due to D2-RECEPTOR BLOCKADE,
both centrally (in the chemoreceptor trigger zone
of the medulla) and peripherally (on receptors in
the stomach). Some drugs, such as prochlorperazine
are promoted only as antiemetics.
Phenothiazines with shorter side chains have considerable H1-receptor-blocking action and used for
(2) relief of pruritus or, in the case of promethazine,
as (3) preoperative sedatives. The butyrophenone
droperidol is used in combination with an opioid,
fentanyl, in neurolept-anaesthesia (-analgesia).
Adverse reactions of neuroleptics:
– behavioral effects:
The older typical antipsychotic drugs are unpleasant
to take. Many patients stop taking these drugs
because of the adverse effects, which may be
soften by giving small doses during the day and
the major portion at bedtime.
•A “pseudodepression” that may be due to druginduced akinesia usually responds to treatment with
antiparkinsonian drugs.Other pseudodepressions may
be due to higher doses; the decreasing the dose may
relieve the symptoms.
•Toxic-confusional states may occur
with very high doses of drugs that have
prominent antimuscarinic actions.
Adverse reactions of neuroleptics cont.
- Neurologic effects:
1. Extrapyramidal reactions occurring early during
treatment with older agents include typical neuroleptics.
a) Parkinson's syndrome, akathisia (uncontrollable
restlessness), and acute dystonic reactions
(spastic retrocollis or torticollis).
NB!!! Parkinsonism can be treated, with
conventional antiparkinsonian drugs of the
antimuscarinic type or, in rare cases, with
amantadine.
Adverse reactions of neuroleptics cont.
b)Tardive dyskinesia
- persistent involuntary
movements of mouth,
tongue or face.
Autonomic nervous system side effects
Antimuscarinic (atropine-like) adverse effects:
urinary retention, dry mouth, midriasis.
Alpha-blockade: Orthostatic hypotension or impaired
ejaculation should be managed by switching to drugs
with less marked adrenoceptor-blocking actions.
Adverse reactions of neuroleptics cont.
Ocular complications
Deposits in the anterior portions of the eye
(cornea and lens) are a common complication of
Chlorpromazine therapy.
Thioridazine is the only antipsychotic
drug that causes retinal deposits,
which in advanced cases may resemble retinitis
pigmentosa. The deposits are usually associated
with “browning” of vision. The maximum daily
dose of thioridazine has been limited to 800 mg
to reduce the possibility of this complication.
Adverse reactions of neuroleptics cont.
Metabolic and endocrine side effects
Weight gain is very common, especially with
clozapine and olanzapine, and requires monitoring
of food intake, especially carbohydrates.
Hyperglycemia may develop.
Hyperprolactinemia in women results in the
amenorrhea – galactorrhea syndrome and
infertility; in men loss of libido, impotence,
gynecomastia and infertility may result.
Toxic or allergic reactions
Agranulocytosis, cholestatic jaundice, and skin
eruptions occur rarely with the high-potency
antipsychotic drugs currently used.
Adverse reactions of neuroleptics cont.
Neuroleptic malignant syndrome
This life-threatening ADR occurs in patients who
are extremely sensitive to the extrapyramidal effects
of antipsychotics. The initial symptom is marked
muscle rigidity. If sweating is impaired, as it often
is during treatment with anticholinergic drugs,
fever may ensue, often reaching dangerous levels.
The stress leukocytosis and high fever associated
with this syndrome suggest an infectious process.
Autonomic instability, with altered blood pressure
and pulse rate, is often present. Creatinekinase
isoenzymes are usually elevated, reflecting
muscle damage.
Adverse reactions of neuroleptics cont.
Neuroleptic malignant syndrome cont.
This syndrome is believed to result from an excessively
rapid blockade of postsynaptic DA receptors. A severe
form of extrapyramidal syndrome follows.
•Early in the course, vigorous treatment of the
extrapyramidal syndrome with antiparkinsonian drugs
is worthwhile.
•Muscle relaxants, particularly diazepam, are often
useful. Other muscle relaxants, such as dantrolene,
or DA agonists, such as bromocriptine, have been
reported to be helpful.
•If fever is present, cooling by physical measures
should be tried.
ANXIOLYTICS
(tranquilizers)
Antianxiety drugs (anxyolitics)
Anxiolytic drugs are designed for treatment of
anxiety, panic disorders and phobias.
 Anxiety is unpleasant emotional state
characterised by uneasiness, discomfort, fear
about some defined or undefined threat.

Antianxiety drugs (classification)
1.BENZODIAZEPINES
a). Short acting
 Oxazepam
 Triazolam
b). Intermediate acting
 Lorazepam
 Alprazolam
 Estazolam
 Temazepam

c). Long acting
 Chlordiazepoxide
(Chlozepidum)
 Clonazepam
 Clorazepate
 Diazepam (Sibazonum)
 Phenazepamum
 Medazepam (Mezapam,
Rudotel)
Antianxiety drugs classification
cont.
2. PROPANDIOL DERIVATIVE
 Meprobamate (Meprotanum)
3. DIPHENYLMETHANE DERIVATIVE
 Benactyzime (Amizylum)
4. AZAPIRONES
 Buspirone
 Gepirone
 Tofizopam (Grandaxin)
5. MISCELLANEOUS
 Trimetozine (Trioxazin)
 Hydroxyzine
 Zolpidem
Mechanism of BZD action
When GABA binds with
the GABAA-receptor, the
permeability of the central
pore of the receptor to
chloride ions increases
(hyperpolarization) and
decreasis excitability.
Benzodiazepines (BDZs) enhance the effectiveness
of GABA by increasing the frequency of the opening
of the chloride ions. BDZs are agonists at the receptor
and the FLUMAZENIL (antagonist) prevents agonists
from binding at the receptor site.
A model of
the GABAA
receptorchloride ion
channel
macromolecular
complex
CNS action and classification
(medical use) of BDZs
The action of all BDZs is qualitatively similar, but there
are prominent differences in selectivity and time
course of effect: different members of BDZs are
used for different therapeutic purposes. In contrast
to barbiturates BDZs exert relatively selective
anxiolytic (antianxiety), hypnotic (euhypnotic), muscle
relaxant, and anticonvulsant (antiepileptic) effects.
Anxiolytic effect have all BDZs:
Alprazolam, Bromazepam (Lexotan – tab. 3 mg),
Chlordiazepoxide, Diazepam, Lorazepam,
Мedazepam (daily tranquillisant), Nordiazepam, etc.
CNS action and classification
(medical use) of BDZs cont.
Hypnotic (euhypnotic) effect:
Bromazepam, Flurazepam, Flunitrazepam
Nitrazepam, Midazolam, Triazolam, etc.
Anticonvulsive (antiepileptic) BDZs:
Clonazepam, Clorazepate, Diazepam,
Lorazepam, Nitrazepam
Central muscle relaxants:
Diazepam, Tetrazepam
Pharmacokinetics of BDZs:
BDZs are effective after administration
by mouth but enter the circulation at very different
rates that are reflected in the speed of onset of
action, e.g. alprazolam is rapid, oxazepam is slow.
The liver metabolizes them, usually to inactive
metabolites, but some compounds produce
active metabolites with long t1/2 which greatly
extends drug action, e.g. chlordiazepoxide,
clorazepate, and diazepam.
Biotransformation of benzodiazepines
Medical uses of tranquilizers
Anxiolytic action
Treatment of neurosis, accompanied by fear,
anxiety, exertion, increased irritability, insomnia;
 In case of headache and heart pain of neurotic
origin, so called organic neurosis;
 In case of abstinence in alcohol and drugs
addicts;
 In case of diencephalons crisis (sybazon).
Tranquilizers do not diminish productive
symptoms of psychosis!

Medical uses of tranquilizers cont.

Hypnotic action – they cause sleep, which is
very close to physiological one according to its
parameters:
Nitrazepam
Phenazepam
Diazepam
Chlozepid

Depression of CNS – for atharalgesia:
Sybazon
Midazolam
Medical uses of tranquilizers cont.
Anti-seizure and myorelaxing action
(depression of CNS structures, braking polysynaptic
spinal reflexes)
sybazon, fenazepam


In a case of seizures of any etiology (epileptic
status, tetanus, poisoning with seizure causing
poisons) sybazon is introduced intravenously
(intramuscularly) – 2-4 ml of 0,5 % solution repeatedly
(maximal daily dose – 14 ml);
To eliminate muscle tension in a case of radiculitis,
arthritis, myositis, bursitis.
Seizures
(tetanus)
drug of a first choice
- Sibazon
SIDE EFFECT OF TRANQUILIZERS

Psychological and physical addiction;
Prophylaxis:
1.
Duration of treatment course should not be more than 2
months;
2.
Repeated course – not earlier than after 3 weeks break.
Sleepiness, reeling walk, retarded reactions;

tranquilizers should not be administered in ambulatories to people whose
professions are connected with quick reactions
Paradox reaction of excitation, insomnia;
Dizziness, decreasing of libido, disturbances of
menstrual cycle;

Uncontrolled urination, defecation, ataxia,
dysartria;

Acute poisoning in case of overdosing.


FLUMAZENIL (ANEXAT)
ANTAGONIST OF BDZs receptors
NB!!! Combination of
tranquilizers with
alcohol-containing
drinks is absolutely
contraindicated
(pathological alcohol intoxication)
Azapirones
Buspirone is a selective partial agonsist of presynaptic
5-HT1A-receptors. By stimulating these receptors it
reduces activity of dorsal raphe 5-HT-ergic neurons.
Buspirone relieves mild to moderate generalized
anxiety, but is ineffective in severe cases (panic
reactions and obsessive compulsive disorder).
Sedative H1-blockers
Hydroxyzine is an H1-blocker
with sedative, antiemetic,
antimuscarinic, and spasmolytic
effects. It is effective
in pruritus, and urticaria.
LITHIUM salts
LITHIUM CARBONATE
INDICATIONS FOR ADMINISTRATION
OF LITHIUM DRUGS

Prophylaxis and treatment of endogen
(affective) psychosis: maniac-depressive,
schizo-affective, organic affective

Prophylaxis and treatment of affective
disturbances in patients with epilepsy, chronic
alcoholism, in psychopaths
Method of lithium drugs
administration
It is administered orally;
 Treatment concentration of lithium in blood –
0,6-0,8 mmol/l (not more than 1,5-1,6 mmol/l);
 The effect develops after few days – 5-6
months;
 Small width of therapeutic action (treatment
with lithium drugs needs the same
attentiveness from the doctor as treatment with
insulin).

Acute poisoning with lithium drugs
It develops if the concentration is over 1,5-2 mmol/l
Development of constant nausea and tremor during treatment
with lithium means that the dose should be decreased
SYMPTOMS OF POISONING
 Nausea, vomiting, diarrhea
 Tremor, general muscular weakness, twitching muscles
 Noise in the ears, unclear vision, somnolence, dysartria
 Changes of handwriting: massive, bold
 Local neurological symptoms, meningism
 Oliguria
 Changes in ECG, arrhythmia, decreasing of BP
 Sopor, coma
 Death – from hypostatic pneumonia
Treatment of intoxication with lithium
drugs







A lot of drinking, 10% solution of sodium chloride (till
300 ml/day), 5% solution of sodium hydrocarbonate
(till 300 ml/day) intravenously;
Mannit, urea (saluretics are contraindicated!);
Pyracetam, vinpocetin;
Prophylaxis of pneumonia – antibiotics;
Control of water-electrolyte balance, acid-base
balance;
Symptomatic therapy, for example, in case of seizures
– sybazon;
Haemodialysis if necessary.
Prophylaxis of intoxication with
lithium drugs
Salt in day ration should not be limited
 A lot of drinking
 Do not indicate saluretics, sweatstimulating drugs
 Heavy physical work or other situations,
accompanied by considerable sweating
should be avoided

SEDATIVE drugs
SEDATIVE DRUGS
classification



Bromides: Na-bromide, K-bromide
Drugs of plant origin: Valeriana, dog nettle,
melissa, passiflora etc.
Combined agents: Valocormidum, Corvalolum
etc.
!!!They do not cause addiction,
somnolence, myorelaxation,
ataxia!!!
Valeriana
MEDICAL USES OF
SEDATIVE DRUGS
Neurosis
 Stress
 Neurasthenia
 Hysteria
 Increased irritability
 Insomnia
 Primary stages of essential hypertension

Bromism (brom acute poisoning)
Cause – accumulation of bromide ions in
organism in case of their prolonged
administration as a result of material
accumulation;
 Symptoms: rhinitis, cough, conjunctivitis, skin
rash, general weakness, memory disorders;
 Treatment: sodium chloride (10-20 g / day), a
lot of drinking (3-5 l / day), regular and
frequent cleaning of skin and digestive tract.

Thank your for attention!!!