CNS StimulantsCNS Stimulants

PSYCHOTROPIC DRUGSDrugs withDrugs with depressivedepressive type of actointype of actoin

1.1. Neuroleptics Neuroleptics ((antipsychoticantipsychotic))2.2. Tranquilizers Tranquilizers ((anxiolyticsanxiolytics))3.3. Sedative drugsSedative drugs4.4. Normotymics Normotymics ((tymolepticstymoleptics, , tymoanalepticstymoanaleptics))

Drug withDrug with stimulativestimulative actionaction1.1. Antidepressants Antidepressants 2.2. Psychomotor stimulantsPsychomotor stimulants3.3. Nootropic drugsNootropic drugs4.4. Drugs which increase general tone Drugs which increase general tone

((adaptogensadaptogens))PsychotomimeticsPsychotomimetics ((psychodyslepticspsychodysleptics))

1.1. LSD LSD 2.2. Cannabis sativa L.Cannabis sativa L.

ANTIDEPRESSANTSANTIDEPRESSANTS

DEPRESSION• Types• Symptoms• Diagnosis• Causes• Treatment

TYPES OF DEPRESSION• Major depression• Chronic depression

(Dysthymia)• Atypical depression• Bipolar disorder/Manic

depression• Seasonal depression (SAD)

CAUSES OF DEPRESSION• Genetics• Death/Abuse• Medications

SYMPTOMS• persistently sad, anxious, or empty moods• loss of pleasure in usual activities (anhedonia)• feelings of helplessness, guilt, or worthlessness• crying, hopelessness, or persistent pessimism• fatigue or decreased energy• loss of memory, concentration, or decision-making capability• restlessness, irritability• sleep disturbances• change in appetite or weight• physical symptoms that defy diagnosis and do not respond to

treatment (especially pain and gastrointestinal complaints)• thoughts of suicide or death, or suicide attempts• poor self-image or self-esteem (as illustrated, for example, by

verbal self-reproach)

More than 50 % of patients with depressive disorders don’t realize that they have any psychological problems and

complain only on certain somatic discharges

Most frequent complaints of patients with depressionFeeling of hopelessness, indifference, fear, panic

Tiredness, weakness, headache, dizziness, dream disorders, dyspepsia, unpleasant feelings and pain in different parts of

the body

Depressive conditions “mask” as vegetovascular, neurocirculative dystonia (various vegetative disorders), gastro-intestinal pathology, pathology of cardio-vascular,

respiratory systems, manifest as diskinesia, functional motor disorders, insomnia, toothache, disorders of sexual activity,

recidivate eczema and many other disorders

TREATMENT FOR DEPRESSION

• Psychotherapy• Electroconvulsive therapy• Natural alternatives• Medication

• SSRIs• MAOIs• TCAs• SNRIs• NDRIs• TeCAs

NEUROTRANSMITTERS AND THE CATECHOLAMINE

HYPOTHESIS• Neurotransmitters pass along signal• Smaller amount of neurotransmitters causes

depression

Function of adrenergic synapse in Function of adrenergic synapse in physiological conditionsphysiological conditions

ANTIDEPRESSANTSANTIDEPRESSANTSDrugs which inhibit neuronal uptake of

monoamines1. Nonselective action (block uptake of noradrenaline and

serotonine): imisin, amitriptilin2. Selective action: а) heterocyclic compounds (block neuronal

uptake of noradrenaline): amoxapin, maprotilin (ludiomil); б) selective blockers of neuronal uptake of serotonin: fluoxetin (prozak, framex), sertralin (zoloft), paroxetin (rexetin)

Inhibitors of monoaminoxidase (IMAO)1. nonselective (block МАО-А and МАО-В): а) irreversible

action – nialamid; b) reversible action – transamin 2. Selective ІМАО (block МАО-А): moklobemid, pirasidol

TCAS MECHANISM OF ACTION

• TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake

• TCAs also allow for the down regulation of post-synaptic receptors

• All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT

TCAS SIDE EFFECTS• Muscarinic M1 receptor antagonism - anticholinergic effects

including dry mouth, blurred vision, constipation, urinary retention and impotence

• Histamine H1 receptor antagonism - sedation and weight gain• Adrenergic α receptor antagonism - postural hypotension• Direct membrane effects - reduced seizure threshold,

arrhythmia• Serotonin 5-HT2 receptor antagonism - weight gain (and

reduced anxiety)

TCAS SIDE EFFECTS• Nonselectivity results in greater

side effects• TCAs can also lead to

cardiotoxicity– Increased LDH leakage– Slow cardiac conduction

• High potency can lead to mania– Contraindicated with persons

with bipolar disorder or manic depression

MONOAMINE OXIDASE (MAO) AND DEPRESSION

• MAO catalyze deamination of intracellular monoamines– MAO-A oxidizes epinephrine, norepinephrine, serotonin– MAO-B oxidizes phenylethylamine– Both oxidize dopamine nonpreferentially

• MAO transporters reuptake extracellular monoamine

MAOIS MECHANISM OF ACTION

• MAO contains a cysteinyl-linked flavin

• MAOIs covalently bind to N-5 of the flavin residue of the enzyme

Mechanism of action of IMAOMechanism of action of IMAO

Blockers of neuronalBlockers of neuronal uptake of uptake of serotonin serotonin

Modern point of view on mechanism of development of depression

Primary deficiency of serotonin in synaptic gap

Compensatory growing of quantity and sensitivity of postsynaptic 5-НТ2 receptors

Compensatory decreasing of quantity and sensitivity of presynaptic 5-НТ1 receptors in hippocampus and

nuclei row (these structures play an important role іn development of depression)

Blockers of neuronalBlockers of neuronal uptake of serotoninuptake of serotonin fluoxetinfluoxetin, , sertralinsertralin, , paroxetinparoxetin

Mechanism of actionIncreasing of active concentration of

serotonin in synaptic gap on a level of postsynaptic

5-НТ2 serotonin receptors of cerebral structures

Blockers of neuronalBlockers of neuronal uptake of serotoninuptake of serotonin fluoxetinfluoxetin, , sertralinsertralin, , paroxetinparoxetin

SSRIS SIDE EFFECTS

SSRIS SIDE EFFECTS• Many disappear within 4 weeks (adaption

phase)• Side effects more manageable compared

to MAOIs and TCAs• Sexual side effects are common• SSRI cessation syndrome

– Brain zaps– Sexual dysfunction

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)

• Slightly greater efficacy than SSRIs• Slightly fewer adverse effects than SSRIs• Current drugs

– Venlafaxine (Effexor)– Duloxetine (Cymbalta)

• Mechanism of Action– Very similar to SSRIs– Works on both neurotransmitters

• Side effects– Similar to SSRIs– Suicide

Usage of antidepressantsUsage of antidepressants

Schizophrenia, Bipolar disease Atherosclerosis of brain

Reactive depressionsParkinsonism

Organic diseases of CNSOncology patients

General somatic diseases

Psychotropic action of Psychotropic action of antidepressantsantidepressants

1. Drugs with psychosedative action:Аmitriptilin, maprotilin, asafen,

fluvoxamin2. Drugs with psychostimulative action:

Imisin, nialamid, fluoxetin3. Drugs with regulative influence

PirasidolPirasidol

Principles of antidepressants usagePrinciples of antidepressants usage

• Endogen depression – the deeper it is, the larger doses, rate of their increasing and duration of treatment should be administered

• Step-by-step dose increasing till obtaining of effect, administration of effective dose during 4-6 weeks – 3-6 months, gradual decreasing of dose (during 5-6 weeks)

• Effect can appear only after 7-14 days after beginning of therapy (this fact should be taken into consideration in patients with suicidal dispositions)

• In case of rapid abolishing withdrawal syndrome may develop

Side effects of antidepressantsSide effects of antidepressants

• М-cholinoblocking action: dry mouth, increasing of intraocular pressure, disturbance of accommodation, constipation, ischuria (important in a case of adenoma of prostatic gland!), tremor, hallucinations, disorders of consciousness, excitation

• Alpha-adrenoblocking, papaverine-like effect: sharp hypotension, orthostatic collapse (especially in combination of amitriptiline with clopheline), for correction of which adrenomimetics can’t be used (it is necessary to increase volume of circulating blood, put the legs up)

Side effects of antidepressantsSide effects of antidepressants

• Acute attacks of epilepsy epilepsy • CardiotoxicCardiotoxic action (sudden death), three-

cyclic antidepressants increase arrhythmogenic activity of drugs for general anesthesia, antihistamines etc.

• Combination of three-cyclic antidepressants Combination of three-cyclic antidepressants with IMAO is absolutely contraindicatedwith IMAO is absolutely contraindicated:: danger of development of hypertensive crisis, seizures, rapid excitation, tachycardia, cardiac arrhythmias, increasing of temperature

Rules of transferring from one kind of antidepressants to another

• From three-cyclic to IMAO – break time– 2-3 days

• From IMAO to three-cyclic – break time – not less than 2 weeks

It is absolutely contraindicated to It is absolutely contraindicated to administer adreno(sympato)mimetics in administer adreno(sympato)mimetics in case of treatment with antidepressantscase of treatment with antidepressants

Even small doses of adrenomimetic (sympatomimetic) substances in such patient can cause hypertensive crisis:hypertensive crisis:

• Nose drops for rhinitis• If few drops were added to solutions of

local anesthetics• In case of administration of drugs which

contain pseudoephedrine

Diet in case of administration Diet in case of administration of IMAOof IMAO

It is necessary to exclude such products which contain

DOPA and thiramine (which is formed from casein during the process of transforming under the influence of bacteria)

aged cheese, kefirMarinated herringSmoked meat, fish

Red vine, beer, yeastBeans

Any BAA are also dangerousIn case of treatment with IMAO new products should In case of treatment with IMAO new products should

be introduced intobe introduced into ration very carefullyration very carefully

• In case of administration of inhibitors of uptake of serotonin the previously indicated side effects are observed much more rarely

• Administration of antidepressants with any other drugs should be performed only after precise studying of possible negative consequences of their interaction

PSYCHOMOTOR PSYCHOMOTOR STIMULANTSSTIMULANTS

PSYCHOMOTOR STIMULANTSPSYCHOMOTOR STIMULANTS

• Derivatives of purine – caffeinecaffeine• Phenilalkilamines – phenaminephenamine

((amphetamineamphetamine))• Phenilalkilsydnonimins - sydnocarbsydnocarb

Properties of psychomotor Properties of psychomotor stimulantsstimulants

• Stimulate intellectual activity, speed up thinking processes, temporarily eliminate tiredness, somnolence

• Eliminate such manifestations of neurosis as: subdepression, fatigue, retardness

• Aren’t able to eliminate endogen depression, which accompanies psychical diseases

CaffeineCaffeine

Did You Know?

• Caffeine is a xanthine alkaloid compound that acts as a stimulant in humans. Caffeine is sometimes called guaranine when found in guarana, mateine when found in mate, and theine when found in tea. It is found in the leaves and beans of the coffee plant, in tea, yerba mate, and guarana berries, and in small quantities in cocoa, the kola nut and the Yaupon Holly. Overall, caffeine is found in the beans, leaves, and fruit of over 60 plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding upon them.

Chemical PropertiesMolar Mass = 194.19 g mol−1 Density: 1.2 g/cm³Phase: Solid

Melting Point: 237 °C Boiling Point: 178 °C

Uses of Caffeine• Caffeine is a central nervous system

(CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity: caffeine is the world's most widely consumed psychoactive substance. In North America, 90% of adults consume caffeine daily.

Metabolizing Of Caffeine• Caffeine is completely absorbed by the stomach and

small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by first-order kinetics. The half-life of caffeine varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 3-4 hours. In women taking oral contraceptives this is increased to 5-10 hours, and in pregnant women the half-life is roughly 9-11 hours. Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours.

Caffeine Caffeine

Mechanism of action • Binds to adenosine adenosine (“(“purinepurine”) ”) receptorsreceptors in

brain (endogen ligand of these receptors – adenosine decreases processes of excitation in CNS)

• Inhibiting of phosphodiesteraseInhibiting of phosphodiesterase, which leads to accumulation of cAMP and stimulation of many physiological processes and metabolism

Usage of psychostimulating Usage of psychostimulating influence of caffeineinfluence of caffeine

• For stimulation of psychological processes, workability, to eliminate somnolence

• Enuresis, narcolepsy• In case of poisoning with alcohol• To speed up awakening after narcosis

Influence of caffeine on cardiac-vascular system

Vessels Vessels 1. Stimulation of vasomotor center –

contraction of vessels, increasing of AP2. Peripheral myotropic spasmolytic action

– dilation of vessels, decreasing of APHeartHeart

1. Central action (increasing of n. vagus tone) – bradycardia

2. Peripheral action (direct influence on heart) – tachycardia, possible extrasystolia

Influence of caffeine on cardio-Influence of caffeine on cardio-vascular systemvascular system

• Contraction of brain vessels• Dilation of kidney vessels, increasing of diuresis• Dilation of coronary vessels

In case of depression of centers of brain stem (medulla oblongata) caffeine

shows stimulating properties, increases blood pressure, stimulates breathing –

analeptic actionanaleptic action

SIDE EFFECTS OF CAFFEINESIDE EFFECTS OF CAFFEINE• If administered regularly – psychological

addiction – theism, which is accompanied by development of abstinent syndrome (retardness, fatigue, somnolence, depression)

• Tolerance• Teratogenic action (innate abnormalities)• Increasing of frequency of IHD, essential hypertension• Acute attacks of ulcer disease (it increases gastric

secretion)• Acute poisoning in case of overdosing

CNS STIMULANTS

• Medically approved use is for the treatment of Attention deficit/hyperactivity disorder (ADHD), narcolepsy, obesity & reversal of respiratory distress

• Drugs used to treat migraine headache

Pathophysiology

• ADHD may be caused by disregulation of the neurotransmitters serotonin, norepinephrine & dopamine. This occurs in children less than 7 y/o but may persist through the teenage years. More common in boys. Characterized by inattentiveness, inability to concentrate, restlessness, hyperactivity, inability to complete tasks & impulsivity.

A: My son is hyperactive.B: Kids are like that sometimes.A: No, I''m serious. He is constantly on the go from 5 a.m. to 10

p.m.

Pathophysiology

• Narcolepsy is characterized by falling asleep during normal waking activities. Sleep paralysis usually accompanies it & affects voluntary muscles.

AMPHETAMINE-LIKE DRUGS

• MOA: stimulate the release of NE & Dopa• For the treatment of ADHD & Narcolepsy• increases attention span, cognitive performance & to decrease

impulsiveness, hyperactivity & restlessness• SE: restlessness, insomnia, tachycardia, hypertension,

palpitation, dry mouth, anorexia, weight loss, diarrhea, impotence

• Antihypertensive & barbiturates decrease action & Caffeine increase its action

• Methylphenidate (Ritalin)Pemoline (Cylert)

AnalepticsAnaleptics ( (BemegridumBemegridum,, Camphora Camphora, , CordiaminumCordiaminum))

CamphoraCamphora

ANALEPTICS• CNS stimulants mostly affecting the brainstem &

spinal cord but also affects the cerebral cortex• Primary use is to stimulate respiration like in

newborns with respiratory distress• SE: nervousness, restlessness, tremors,

palpitations, insomnia, diuresis, GI irritation• Methylxanthines – caffeine, theophylline

RESPIRATORY CNS STIMULANT

• CNS & respiratory stimulant used to treat respiratory depression caused by drug overdose, pre- & postanesthetic respiratory depression & chronic obstructive pulmonary disease (COPD)

• Doxapram HCl (Dopram)

NOOTROPIC DRUGSNOOTROPIC DRUGS

((NEUROMETABOLIC NEUROMETABOLIC CEREBROPROTECTORS)CEREBROPROTECTORS)

Neurometabolic cerebroprotectors

• Derivatives of pyrrolidone – pyracetam (nootropil)• Derivatives of GABA – aminalon, sodium

oxybutyrate• Neuropeptides – melatonin, sinacten-depot• Cerebrovascular drugs – sermion (nicergolin),

cavinton (vinpocetin), stugeron (cinnarisin), pentoxyphylline (trental, agapurine), xantynole nicotinate

• Derivatives of piridoxine – piritinol (encephabol)• Antioxidants – mexidol, tocopherole acetate• Other – cerebrolysine, actovegin, solkoseryl, plant

preparations

Properties of nootropic drugsProperties of nootropic drugs• Improvement of brain blood circulation,

promotion of collaterals development• Psychostimulating effect, antiasthenic action• Sedative, antidepressive action• Antiepileptic, antiparkinsonic action• Nootropic action• Mnemotropic action• Vasovegetative action• Antihypoxic action

Administration of nootropic drugsAdministration of nootropic drugs

• Atherosclerosis of brain, vascular parkinsonism, Alzheimer's disease

• Disorders of brain blood circulation in case of traumas and intoxications, vascular diseases of brain

• Diseases of CNS, accompanied by decreasing of intellect, memory

• Disorders of psychology (in elderly with schizophrenia, depressions)

• To decrease manifestations of abstinence (alcoholism, drug addiction)

• In neurology (neurasthenia, migraine, neuralgias, radiculitis)

• In pediatrics in case if mental insufficiency

Piracetam Piracetam ((nootropilnootropil))

CerebrolysinCerebrolysin

CinnarizinCinnarizin ( (stugeronstugeron))

ADAPTOGENSADAPTOGENS

AdaptogensAdaptogensDrugs of

Ginseng, Schizandrum, Rodiola, Eleutherococcus, Leusea,

Echinacea

Apilac, propolis, mumie, heparin, dybazol

GINSENGGINSENG

RODIOLARODIOLA

EleutherococcEleutherococc

Schizandrum

Echinacea purpurea MaximaEchinacea purpurea Maxima

ADAPTOGENSIncrease general resistance of the organism

towards unfavorable factors

Stimulating actionAntistress action Anabolic action

Side effects of adaptogens

Increasing of AP disturbance of sleep if administered

in evening time, overwhelming excitation, psychic dependence