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Antidepressants. Antianxiety,
Psychostimulants and
Psychodyleptics
Anton Kohút
Depression
is pervasive mood altering ilnesses affecting
energy, sleep, appetite, libido and the ability
to function
Antidepressants.
Depression
Symptoms:
 depression
intensive feelings of sadness
hopelessness
inability to experience pleasure in usual activities
 mania
enthusiasm
rapid though and speech paterns
 it is an affective disorders characterized by changes
in mood (depression or mania)
 - about 10% of population - experience with depression
 woman:man ratio - 2:1
Depression is due to a decrease of
noradrenaline, serotonine,
 Mania is due to oposite changes,
 The bases of the treatment of
depression is increase of Na and 5-HT.
?
 first great theory - role of monoamine
neurotransmitters (NE, 5-HT)
 defficiency of neurotransmitters - depression
 simplistic theory
 problem - timming of antidepressant effect on
neurotransmitts is far from the timing of the
antidepressant effect on mood
 newer theories - role of neurotransmitter receptors
 disturbancies in signal transducion
Classification of antidepressants
1.
Tricyclic antidepressants (TCAs)
– Imipramine, Nortriptyline, Amitriptyline, Doxepin
Clomipramine Desipramine
2. Monoamine oxidase inhibitors (MAOIs)
– Phenelzine, Tranylcypromine
3. Selective serotonin (5-HT) reuptake inhibitors
(SSRIs)
– Fluoxetine, Fluvoxamine, Sertraline, Paroxetine
4. Reversible monamine oxidase inhibitors (RIMAs)
– Moclobemide
New antidepressants
5. Norepinephrine Reuptake Inhibitors (NRI)
-Reboxetine
6. Norepinephrine and Dopamine Reuptake Inhibitors
(NDRI) - Bupropion
7. Serotonin / norepinephrine reuptake inhibitors
- Venlafaxine
8. Noradrenergic and Specific Serotoninergic
Antidepressants (NaSSA) –Mirtazapine, Mianserine
9. Serotonin-2A antagonists/serotonin reuptake
inhibitors
– Trazodone
10. Serotonin-2A antagonists/norepinephrine reuptake
inhibitors
– Nefazodone
Classification of antidepressive drugs
Tricyclic antidepressants (TCAs)
• TCAs prevent the reuptake of NA and 5HT from the synaptic
cleft
• This re-uptake
blockade leads to the
accumulation of 5-HT
and NA in the
synaptic cleft
Tricyclic antidepresants (TCA)
 inhibition of re-uptake  increase of NE, 5-HT
 also blockade of M, H1 1 receptors
 2-3 weeks for antidepressive action
 many years  drug of choice
 M-receptors  dry mouth, urine retention, constipation,
blurred vision
 M+1-receptors - tachycardia, hypertension, postural
hypotension,
 H1-receptors  sedative effects, body weight gain
Side effects of TCAs
1. Anticholinergic
-mucosal dryness
-constipation
-urinary retention
-confusion
-blurred vision
-aggravation of glaucoma
2. Anti alpha adrenergic
- orthostatic hypotension
3. Antihistaminic
-sedation
4. Quinidine-like
- cardiac arrhytmias and
block
Selective Serotonin Reuptake Inhibitors
(SSRI)
 inhibiion of 5-HT re-uptake
 increase of 5-HT  effect on postsynaptic 5-HT and 5HT1A presynaptic receptors
 stimulation of 5-HT1A receptors  „down-regulation“ 
lower effect on 5-HT release from presynaptic neurons
 inhibition of NE reuptake 
 blockade of 1, H1 alebo M- receptors   cardotoxic,
hypotensive, sedative effects
 most often prescribed antidepressants today
 SEROTONINE SYNDROME – combination of SSRI +
MAO - lifethreating consequences  tremor,
convulsions, abdominal pain, diarhea, hypertension,
tachycardia, cardiovacular colaps
.
Fluoxetine
 in depresion of different etiology
PK
 food prolongs time of absorpion
 95% to plasma albumine
 metabolised in the liver  major metabolite
(norfluoxetine)  simmilar effect as a fluoxetine
Side effects
 lower incidence and intensity
GIT - nausea, anorexia,
CNS - insomnia, tremor, headache, vertigo
CVS - orthostatic hypotension
MAO inhibitors (IMAO)
 first antidepressive agents used clinically
 "clasical" (e.g. tranylcypromine)  irreverzible,
nonselective inhibition of MAO-A and MAO-B
 for antidepressive effects - inhibition of MAO-A
 2-3 weeks for antidepressive action
 use of "clasical" MAOI is now limited - side effects,
interactions (food, drugs)
 tyramine (contained in some foods - chees, red wine,
beer) is normally inactivated by MAO-B in the gut
 MAO inhibitors elevated tyramine  tyramine causes
release of stored catecholamines
tachycardia, hypertension,
headache, cardiac arrhythmias
 patients must avoid tyramine-containing foods
RIMA (Reversible Inhibitors of MAO-A)
Moclobemide
 specific inhibition of MAO-A (reversible)
 inhibition of deamination of 5-HT, NE, D
PK
 good absorption in GIT
 50% bound to plasma albumine
 95% excreted in urine as an inactive metabolites
Side effects
 insomnia, nausea, headache, dizziness, desorientation,
nervousness
 effect on CVS in combination with tyramine - less
important
New antidepressants
Norepinephrine Reuptake Inhibitors (NRI)
Reboxetine
 introduced in 1997
 inhibition of NE re-uptake
 minimal effect on 5-HT a D
 depression, narcolepsy, panic fear
 98% bound to 1 acid glycoproteine
Side effects
 well tolerated
 obstipation, dry mouth, urine retention, insomnia,
tachycardia
Norepinephrine and Dopamine Reuptake
Inhibitors (NDRI)
Bupropion
 weak inhibitor of D and NE re-uptake
 major metabolite - strong NE re-uptake inhibitor
 suitable for patients with intolerability or low response to
SSRI
 suitable to supress withdrawal symptoms in nicotinedependent people
 contraindicate in epileptic patients - proconvulsive effect
Serotonin and Norepinephrine Reuptake
Inhibitors (SNRI)
 action similar to TCA - NE and 5-HT re-uptake inhibition
 no effects on M, H1 and 1-adrenergic receptors
Venlafaxine
 low doses  5-HT, moderate doses  NA, high doses  D
 metabolised in the liver - O-desmethylvenfalaxine - active metabolit
Side effects
 nausea, constipation, somnolece, nervousness, headache
 serotonine syndrome
Noradrenergic and Specific
Serotoninergic Antidepressants (NaSSA)
 blockade of 2-receptorov   release of NE a 5-HT
Mirtazapine
 high affinity to 2-receptors
 antagonist of 5-HT2, a 5-HT3 and h1-receptors
Side effects
 somnolence, dry mouth, increase of apetite, body weight gain, constipation,
serotonine syndrome
Mianserine
 selective antagonist of presynaptic 2-adrenergic receptors
 partial effect on 1, 5-HT2, 5-HT3 h1- receptorov
 main metabolites  biological activity
Side effects
 hypersensitivity, nausea, tremor
Utilization of antidepressants
Edvard Munch
Anxiety
unpleasant state of tension,
apprehension, or uneasiness. Disorders
involving anxiety are the most common
mental disturbances
Causes of Anxiety
2). Drug-Induced:
– Stimulants
 Amphetamines, cocaine, TCAs, caffeine.
– Sympathomimetics
 Ephedrine, epinephrine, pseudoephedrine
phenylpropanolamine.
– Anticholinergics\Antihistaminergics
 Trihexyphenidyl, benztropine, meperidine
diphenhydramine, oxybutinin.
– Dopaminergics
 Amantadine, bromocriptine, L-Dopa, carbid/levodopa.
3). Drug Withdrawal:
 BDZs,
narcotics, BARBs, other sedatives,
alcohol.
Anxiolytics
1) Benzodiazepines (BZDs).
2) Barbiturates (BARBs).
3) 5-HT1A receptor agonists.
4) 5-HT2A, 5-HT2C & 5-HT3 receptor
antagonists.
If ANS symptoms are prominent:
• ß-Adrenoreceptor antagonists.
• 2-AR agonists (clonidine).
Benzodiazepines
Benzodiazepines (BZD)
Mechanism of action
BDZ receptors
Benzodiazepines
Actions
 Reduction of anxiety
 Sedative and hypnotic actions
 Anticonvulsant
 Muscle relaxant (relax spasticity
of ckeletal muscle).
Pharmacokinetic aspects
 Are well absorbed from GIT,
 They bind strongly to plasma
protein, have high lipid
solubility, fast cross blood-brainbarrier: rapid onset of action
 The effect of long-acting
increases with the age.
Therapeutic uses
 Anxiety
 anxiety that accompaniges some
forms of depression.
 Muscular disorders-muscle spasm,
spasticity from degenerative
disorders,
 Seizures- grand mal epilepic seizures,
 acute treatment of alcohol withdrawal
 Sleep disorders.
Side effects
 Disturbance of intellectual
functioning and motor activity
impairs manual skils,
 Potential for dependence and
withdrawal syndrome.
Properties of Benzodiazepines
• BDZs have a wide margin of safety if used for short periods. Prolonged
use may cause dependence.
• BDZs have little effect on respiratory or cardiovascular function
compared to BARBS and other sedative-hypnotics.
• BDZs depress the turnover rates of norepinephrine (NE), dopamine
(DA) and serotonin (5-HT) in various brain nuclei.
• Keep in mind that with formation of active metabolites, the kinetics of the
parent drug may not reflect the time course of the pharmacological
effect. Prototype drug is diazepam (Valium), which has active
metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½
= 20-80 hr).
• Estazolam, oxazepam, and lorazepam, which are directly metabolized
to glucoronides have the least residual (drowsiness) effects.
• All of these drugs and their metabolites are excreted in urine.
•
Metabolizmus BDZ
From Katzung, 1998
Classification of anxiolytic and hypnotic drugs
I. Benzodiazepines
a. Used as anxiolytics: alprazolam,
chlordiazepoxid, diazepam,
lorazepam
b. Used as hypnotics: flurazepam,
nitrazepam, temazepam
Long – acting (1-3 days):
diazepam, nitrazepam,
flurazepam
Intermediate acting (10 20 hours):
alprazolam, lorazepam
Flumazenyl –BDZ antagonist
II. Other Anxiolytic drugs
( buspirone (5-HT1A agonist),
Buspirone
“second generation anxiolytics”
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has strong anxiolytic properties
almost no sedative effect, drowsiness or hypnosis
minimal amnesia and dementia
does not potentiate other sedatives
no abuse potential
it is 5-HT1A agonist
has both antianxiety and antidepressant effects
used for a variety of conditions
metabolized very quickly, grapefruit juice increases
effect
 slow onset of action
Jennifer Glasgow
Hypno-sedative drugs
They produce a pronounce, graded,
dose-dependent depression of the
central nervous system.
Hypno-sedative drugs
terminology
Sedation
can bedefined as a supression of responsiveness to a
constant level of stimulation, with decreased
spontaneous activity
Hypnotic effects
involve more pronounced depression of the CNS than
sedation, and this can be achieved with most sedative
drugs simply increasing the dose.
Hypno-sedatives
I.
generation – barbiturates (obsolete)
II.
generation – benzodiazepines
(BDZs)
III.
generation – zolpidem, zaleplon
Hypnotics
a. Barbiturates .
- Long acting (1-2 days) : phenobarbital.
- Intermediate acting (3-8 hours): amobarbital,
aprobarbital, pentobarbital,.
- Ultrashot acting (20 minutes): thiopental
b. Other sedatives and hypnotics
Antihistamines
Ethanol
Barbiturates
• In the elderly and in those with limited hepatic function,
dosages should be reduced.
• Phenobarbital and meprobamate cause autometabolism by
induction of liver enzymes.
• Strong physiological dependence may develop
upon long-term use.
• Depression of the medullary respiratory centers is
the usual cause of death of sedative/hypnotic
overdose. Also loss of brainstem vasomotor control
and myocardial depression.
Toxicity/Overdose
• Withdrawal is characterized by increase anxiety,
insomnia, CNS excitability and convulsions.
• Drugs with long-half lives have mildest withdrawal.
• Drugs with quick onset of action are most abused.
• No medication against overdose with BARBs.
• Contraindicated in patients with porphyria.
Sedative/Hypnotics
SLEEP PER NIGHT
(%)
Tolerance and excessive rebound occur in response to
barbiturate hypnotics.
CONTROL
WITHDRAWAL
REM
NREM III and IV
1
2
3
NIGTHS OF DRUG DOSING
Respiratory
Depression
BARBS
Coma/
Anesthesia
BDZs
Ataxia
Sedation
Anticonvulsant
Anxiolytic
DOSE
Miscellaneous Drugs
Buspirone
 Chloral hydrate
 Hydroxyzine
 Meprobamate (Similar to BARBS)
 Zolpidem (BZ1 selective)
 Zaleplon (BZ1 selective)

Zolpidem
• Structurally unrelated but as effective as BDZs.
• Minimal muscle relaxing and anticonvulsant effect.
• Rapidly metabolized by liver enzymes into inactive
metabolites.
• Dosage should be reduced in patients with hepatic
dysfunction, the elderly and patients taking cimetidine.
Psychostimulants
Psychostimulants – general
considerations
• are drugs:
• that produce wakefullness and arousal and stimulate
behavior,
• their current clinical use is limited to treatment of specific
sleep disorders such as narcolepsy, and certain
childhood behavioral problems such as attention deficit
disorder,
• more importantly, the psychomotor stimulants are a class
of drugs widely self-administered for non-medical
reasons.
• including cocaine, amphetamine,
methylphenidate,fenfluramine, phentermine, ephedrine
and cathinone
Amphetamines
Amphetamine
• (1) induce the release of
dopamine and NA from the
nerve terminal;
• (2) amphetamine can interact
with dopamine containing
synaptic vesicles, releasing
free dopamine into the nerve
terminal;
• (3) prevent the degradation of
dopamine,
• (4) inhibits re-uptake
transporter.
Pharmacological actions
 the primary effects of an oral dose are:
wakefulness, alertness, decrease fatigue
mood elevation, increased ability to concentrate
an increase in motor and speech activity
 amphetamines also diminish the awareness of fatigue person may push exertion to the point of severe damage
or even death.
stimulate the respiratory center,
especially when respiration is depressed
by centrally acting drugs, (barbiturates
and alcohol)
 amphetamine can reverse the marked
sedation and behavioral retardation
resulting from reserpine-like drug
depresses appetite by their action on the
lateral hypothalamus rather than an
effect on metabolic rate
Side effects
 CVS: cardiac stimulation leads to headache,
palpitations, cardiac arrhythmias, anginal pain
 CNS: euphoria, dizziness, tremor, irritability, insomnia,
convulsion (at higher doses), hyperthermia and coma
 addiction - including psychic dependence, tolerance
and physical dependence.
 others: weight loss, psychotic reaction which are often
misdiagnosed as schizophrenia.
Therapeutic Uses
 hyperkinesias - methylphenidate
 narcolepsy - amphetamine or
methylphenidate
 obesity - fenfluramine
METHYLXANTINS
METHYLXANTINS
Caffeine is found in varying
quantites in the beans, leaves,
and fruit of over 60 plants,
Caffeine
Metabolites:
• theobromine - vasodilator
• theophylline -, smooth muscle
relaxant
• paraxanthine - increase the
lipolysis
METHYLXANTINES
Caffeine:
Coffee (100-150 mg/cup)
 Tea (30-40 mg/cup)
Cocoa (15-18mg/cup)
Theophylline: Tea and cocoa
Theobromine: Cocoa
Mechanisms of action of metylxantins
Caffeine acts through multiple
mechanisms:
is an antagonist of adenosine
receptors. It results in increased
activity of the dopamine
Caffeine can also increase levels of
epinephrine/adrenaline - inhibitor of the
enzyme cAMP-phosphodiesterase
causes intracellular calcium release
(independent of extracellular calcium)
caffeine intensifies and prolongs the
effects of epinephrine and epinephrinelike drugs such as amphetamine,
methamphetamine, or methylphenidate
Pharmacological Activity/
Adverse Effects
 Low Doses: 100-250mg/caffeine (oral doses) - increase
mental alertness, decrease drowsiness lessen fatigue
 Larger Doses: 250-600mg/caffeine - irritability,
restlessness, tremor, insomnia, headache, palpitations
 Large Doses: > 1000 mg - excitement, delirium and
clonic seizures
Cardiovascular System:
Increase rate and force of the heart by
directly stimulating myocardium (low
doses)
Tachycardia and arrhythmias at higher
doses.
Peripheral vasodilation - decrease blood
pressure (acute administration)
Hypotension and cardiac arrest (rapid i.v.
theophyline)
muscle (theophylline > caffeine)
Kidney: all xanthines are capable of
producing some degree of diuresis in
humans (Smooth Muscles: relaxes
vascular smooth theophylline > caffeine)
Miscellaneous: xanthines shorten clotting
time by increasing tissue prothrombin and
factor V.
Side effects
 stimulate gastric secretions in patients with ulcer
 dehydration in children due to vomiting and transient
diuretic action (theophyline)
 allergic reaction (aminophylline)
 psychic dependence (caffeine)
 high doses
 emesis, convulsion,
 lethal dose is about 10 g (about 100 cups of coffee) induces arrhytmias
Therapeutic uses
caffeine + plus ergot alkaloid (ergotamine):
 used to treat migraine headaches
theophylline:
 prophylaxis for chronic asthma
 respiratory stimulant
 bronchodilator for relief of asthmatic symptoms
Caffeine - addiction
Cocaine
Kokaín
COCA
Coca Bush (Erythroxylon)

Main pschoactive
substance:
COCAINE

Content (%):
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coca leaves 0.5 - 2.5
coca paste 30 - 80
crack up to 90
COCA
PHARMACOLOGICAL EFFECTS

Sought-after effects

feelings of physical  mental well being, euphoria
increased alertness  energy
suppresion of hunger  fatigue
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Short-term effects
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loss of appetite
faster breathing, increased heart rate  BP
increased body temperature, sweating, dilation of pupils
bizarre, violent behaviour
larger doses: hallucinations, sense of power  superiority,
restlessness, hyperexcitability, irritability, panic  paranoid
psychosis (disappears if discontinued)
excessive doses - convulsions, seizures, stroke, cerebral
hemorrhage or heart failure
Mechanism of action of
cocaine
COCA
PHARMACOLOGICAL EFFECTS
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Long-term effects
destruction of tissues in nose if sniffed
respiratory problems if smoked
infectious diseases, abscesses, if injected
malnutrition, weight loss
disorientation, apathy, confused exhaustion due to lack
of sleep
development of tolerance
strong psychological dependence
with continued use a state similar to paranoid psychosis
may develop
after stopping - long period of sleep  then depression
Cocaethylene
COCA
MEDICAL USE
Cocaine as a local anaesthetic, in particular:

in surgery of the ear, nose and throat
 never inject !
Hallucinogens
Natural and Synthetic
Hallucinogens are drugs that cause
hallucinations. An hallucination is a
sensory experience of something
that does not exist outside the
mind.
• it may involve hearing, seeing, smelling, tasting
or feeling something that isn't really there.
• or, it may involve distorted sensory perceptions,
so that things look, sound, smell, taste, or feel
differently from the way they are.
• usually produce so-called pseudo-hallucinations.
user knows that what he or she is seeing,
hearing, smelling, etc. is not real, but is a
product of the drug.
• London on hallucinogens
Natural hallucinogens
• Mescaline (san pedro
cactus)
• Psilocybin (magic
mushrooms)
Henbane (Hyoscyamus niger)