Antidepressants. Antianxiety, Psychostimulants and Psychodyleptics

Antidepressants. Antianxiety, Psychostimulants and

PsychodylepticsAnton Kohút

Depression is pervasive mood altering ilnesses affecting energy, sleep, appetite, libido and the ability

to function

Antidepressants.

Depression Symptoms: depression

intensive feelings of sadnesshopelessnessinability to experience pleasure in usual activities

 maniaenthusiasmrapid 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 antidepressants1. 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 re-uptake of NA and 5-HT 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 5-HT1A

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 intensityGIT - nausea, anorexia, CNS - insomnia, tremor, headache, vertigoCVS - 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, DPK 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 nicotine-

dependent 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-HTMirtazapine 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

Anxietyunpleasant state of tension,

apprehension, or uneasiness. Disorders involving anxiety are the most common

mental disturbances

Causes of AnxietyCauses of Anxiety2). 2). Drug-InducedDrug-Induced::

– StimulantsStimulants Amphetamines, cocaine, TCAs, caffeine.Amphetamines, cocaine, TCAs, caffeine.

– SympathomimeticsSympathomimetics Ephedrine, epinephrine, pseudoephedrine Ephedrine, epinephrine, pseudoephedrine

phenylpropanolamine.phenylpropanolamine.– Anticholinergics\AntihistaminergicsAnticholinergics\Antihistaminergics

Trihexyphenidyl, benztropine, meperidine Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin.diphenhydramine, oxybutinin.

– DopaminergicsDopaminergics Amantadine, bromocriptine, L-Dopa, Amantadine, bromocriptine, L-Dopa,

carbid/levodopa.carbid/levodopa.3). 3). Drug WithdrawalDrug Withdrawal::

BDZs, narcotics, BARBs, other sedatives, BDZs, narcotics, BARBs, other sedatives, alcohol.alcohol.

AnxiolyticsAnxiolytics1)1) Benzodiazepines (BZDs).Benzodiazepines (BZDs).2)2) Barbiturates (BARBs).Barbiturates (BARBs).3)3) 5-HT5-HT1A 1A receptor agonists.receptor agonists.4)4) 5-HT5-HT2A2A, 5-HT, 5-HT2C 2C & 5-HT& 5-HT3 3 receptorreceptor antagonists.antagonists.If ANS symptoms are prominentIf ANS symptoms are prominent::• ß-Adrenoreceptor antagonists. ß-Adrenoreceptor antagonists. 22-AR agonists (clonidine).-AR agonists (clonidine).

Benzodiazepines

Benzodiazepines (BZD)Mechanism of action

BDZ receptors

BenzodiazepinesActions 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-brain-barrier: 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. Benzodiazepinesa. 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”

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 drugsHypno-sedative drugs

terminologySedation can bedefined as a supression of responsiveness to a constant level of stimulation, with decreased spontaneous activityHypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with most sedative drugs simply increasing the dose.

Hypno-sedativesHypno-sedatives

I.I. generationgeneration – – barbiturates barbiturates (obsolete)(obsolete)

II.II. generationgeneration – – benzodiazepinesbenzodiazepines (BDZs)(BDZs)

III.III. generationgeneration – – zolpidem, zaleplonzolpidem, 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/HypnoticsTolerance and excessive rebound occur in response to

barbiturate hypnotics.

NIGTHS OF DRUG DOSING

SLEE

P PE

R N

IGH

T

(%)

CONTROL WITHDRAWAL

NREM III and IV

REM

1 2 3

Respiratory

Depression

Coma/

Anesthesia

Ataxia

Sedation

Anxiolytic

Anticonvulsant

DOSE

RES

PON

SE

BARBS

BDZs

Miscellaneous DrugsMiscellaneous Drugs BuspironeBuspirone Chloral hydrateChloral hydrate HydroxyzineHydroxyzine Meprobamate (Similar to Meprobamate (Similar to

BARBS)BARBS) Zolpidem (BZZolpidem (BZ11 selective) selective) Zaleplon (BZZaleplon (BZ1 1 selective)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,

CaffeineMetabolites: • 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 cocoaTheobromine: 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 epinephrine-like 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

COCACOCACoca Bush (Erythroxylon)Coca Bush (Erythroxylon)

Main pschoactive Main pschoactive substance:substance:

COCAINE COCAINE Content (%):Content (%): coca leaves coca leaves 0.5 - 2.50.5 - 2.5 coca paste coca paste 30 - 8030 - 80 crackcrack up to 90 up to 90

COCACOCAPHARMACOLOGICAL EFFECTSPHARMACOLOGICAL EFFECTS

Sought-after effectsSought-after effects feelings of physical feelings of physical mental well being, euphoria mental well being, euphoria increased alertness increased alertness energy energy suppresion of hunger suppresion of hunger fatigue fatigue

Short-term effectsShort-term effects loss of appetiteloss of appetite faster breathing, increased heart rate faster breathing, increased heart rate BP BP increased body temperature, sweating, dilation of pupilsincreased body temperature, sweating, dilation of pupils bizarre, violent behaviourbizarre, violent behaviour larger doses: hallucinations, sense of power larger doses: hallucinations, sense of power

superiority, restlessness, hyperexcitability, irritability, superiority, restlessness, hyperexcitability, irritability, panic panic paranoid psychosis (disappears if discontinued) paranoid psychosis (disappears if discontinued)

excessive doses - convulsions, seizures, stroke, cerebral excessive doses - convulsions, seizures, stroke, cerebral hemorrhage or heart failurehemorrhage or heart failure

Mechanism of action of Mechanism of action of cocainecocaine

COCACOCAPHARMACOLOGICAL EFFECTSPHARMACOLOGICAL EFFECTS

Long-term effectsLong-term effects destruction of tissues in nose if sniffeddestruction of tissues in nose if sniffed respiratory problems if smokedrespiratory problems if smoked infectious diseases, abscesses, if injectedinfectious diseases, abscesses, if injected malnutrition, weight lossmalnutrition, weight loss disorientation, apathy, confused exhaustion due to disorientation, apathy, confused exhaustion due to

lack of sleeplack of sleep development of tolerancedevelopment of tolerance strong psychological dependencestrong psychological dependence with continued use a state similar to paranoid with continued use a state similar to paranoid

psychosis may developpsychosis may develop after stopping - long period of sleep after stopping - long period of sleep then then

depression depression

CocaethyleneCocaethylene

COCACOCAMEDICAL USEMEDICAL USE

Cocaine as a local anaesthetic, in Cocaine as a local anaesthetic, in particular:particular:

in surgery of the ear, nose and throatin surgery of the ear, nose and throat never inject !never inject !

HallucinogensNatural 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)