cns stimulants and psychotomimetic drugs
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cns partyTRANSCRIPT
CNS stimulants and
psychotomimetic drugs
PharmDr. Martina Čečková, Ph.D.
Department of Pharmacology and ToxicologyCharles University in Prague
Pharmaceutical faculty in Hradci Králové
22-5-2014
Drugs that predominantly stimulate CNS
1. Psychomotor stimulants- affect mental functions and behaviour
- produce excitement and euphoria, restrict sensation of fatigue, increase
motor activity
2. Psychotomimetic (hallucinogenic) drugs- Affect thought patterns and perception, distore cognition in a complex
way
1. PSYCHOMOTOR STIMULANTS
AMPHETAMINES and related drugs
- Drugs with similar chemical and pharmacological characteristics
• amphetamine, dextroamphetamine
• methamphetamine
• methylphenidate
- Release monoamines (D, NA) from nerve terminals in the brain
acute effect
- Prolonged use - neurotoxic effect, degeneration of amine-containing
nerve terminals, cell death
Pharmacological effectCentral effects
• euphoria and excitement
• locomotor stimulation
• Insomnia, increased stamina
• anorexia
Peripheral sympathomimetic action
- increased blood preasure, inhibition of gastrointestinal motility
• Feeling of anxiety, irritability and restlessness
• paranoia and panic (at high doses)
The amphetamine effect can be blocked by pretreatment with 6-
hydroxytryptamine (depletion of NA, D), α-methyltyrosine (inhibition
of catecholamine biosynthesis)
MAOI potentiate amphetamine effect
(x reserpin does not block the behavior effect of amphetamine)
Adverse effect
Chronic administration, tolerance and dependence
• Repeated administration of amphetamine over the course of few days
o „amphetamine psychosis“ – similar to the atack of schizophrenia
(hallucinations with paranoid symptoms and aggressive
behaviour)
o repetitive stereotyped behaviour
o when the drug administration is stopped - deep sleep, after
awaking letargia, depression and anxiety
• Rapid tolerance to euphoric and anorectic effects (but more slowly to
locomotor stimulation and peripheral sympathomimetic effects
• Dependence – consequence of the insistent memory of euphoria and unpleasant after- effect ( desire to repeated dose)
Pharmacokinetic aspects
• Amphetamine absorbed p.o.
• for increased intensity of the hit – snorted, injected (in crystal form also
smoking)
• Free penetration through BBB, duration of the stimulation effect few
hours
• Urinary excretion – acceleration by urine acidification
Clinical use
• ADHD („attention deficit hyperkinetic disorder“)
o metylphenidate - part of complex therapy
o (another drug in this indication: atomoxetin – inhibitor of
NA re-uptake)
• Narcolepsia
modafinil – (inhibitor of amine uptake)
sodium oxybate (sodium salt of γ-oxybutyrate - CNS depressant)
Unwanted effects of amphetamines
Hypertension (cerebral hemorrhagia), insomnia, anorexia, tremors,
cognitive impairment
COCAINE
alkaloid in the leaves of Erythroxylon coca
Pharmacological effects
- cocaine inhibits active uptake of monoamines dopamine and
noradrenaline into nerve terminals:
increased peripheral effect of sympathetic nerve activity
remarkable psychomotor stimulant effect
- Euphoria, increased motor activity, magnification of pleasure, users
feel alert, believe in enhanced mental capacities
- Amphetamine-like effect, but less tendency to produce stereotype
behaviour, hallucination, delusions and a paranoia
- Peripheral sympatomimetic activity (vasoconstriction, increased
blood preasure, tachycardia)
Excessive dosage
• tremor, convulsions, tachycardia, respiratory and vasomotor depression;
vasoconstriction, increased blood preasure
Chronic use, dependence and tolerance
Strong psychological dependence (craving drug´s euphoric and stimulatory effect)
No clear cut-off syndrome, but depression, dysphoria and fatigue occur after initial stimulant effect
Adverse effectsAcute – cardiovascular events (dysrhythmia, infarction, hemorrhage),
progresive myocardial damage heart failure
Severe impairment of brain development in utero, malformation of limbs,
ischemic and hemorrhagic lesion of brain; increased incidence of
sudden infant death
Pharmacokinetics- rapid absorption
- hydrochloride –nasal inhalation and i.v. administration
- free base („crack “– absorption through the large alveolar suface –
enhanced CNS effect)
- Stimulatory effect duration - 30min
- Fast hepatic biotransformation
- Deposites of cocaine metabolite in hair – monitoring of cocaine
consumption pattern
METHYLXANTHINES
caffeine, theophylline– in beverages like tee, cofee, cocoa low central stimulatory effect
Pharmacological effects•CNS stimulation
•Diuresis (vasodilatation of afferent glomerular arteriols)
•Stimulation of cardiac muscle
•Relaxation of smooth muscle (bronchi)
Mechanism of action:o Inhibition of phosphodiesterase increased cAMP efect similar to
adenylate cyclase stimulation (mimics β- adrenergic stimulation)
o Antagonism of adenosine on A1 and A2 receptors (CNS stimulatory effect)
o At higher concentration (> 10mmol/l) stimulation of rhyanodine receptors
(RyRs)
Minimal tolerance and dependence development
Clinical use
caffeine – in some preparations for treating headaches (with aspirin) and
migrena (with ergotamine)
Theophylline (aminophylline) – bronchodilatator (asthmatic attack)
OTHER STIMULANTS
Arecoline
– in the betel nut (Areca catechu) in India,
Thailand, Indonesia..
– cholinergic agonist, mild stimulant, improves
learning and memory
Cathine
– in the leaves of katha edulis (SE Africa) – chewing the leaves
2. PSYCHOTOMIMETIC DRUGS
(HALUCINOGENS, PSYCHEDELICS)
- Affect though, perception and mood, without causing marked
psychomotor stimulation or depression
- Distorted thoughs and perceptions (dream-like)
- more complex change in mood (not only simple shift in the direction of
depression or euphoria)
- Do not cause dependence
Drugs:
Acting on 5-hydroxytryptamin (5-HT) and its receptors - LSD, Psilocybin,
mescalin; MDMA
Inhibiting NMDA glutamate receptors – Ketamin, fencyklidin
Stimulating cannabinoid receptors (CB)– THC
Stimulating κ – opioid rcp – Salvinorin A
LSD –derivative of lysergic acid
Exceptionally potent psychotomimetic drug – strong effect in doses lowerthan 1µg/kg
mescaline – chemicaly related to amphetamine, derived from a Mexicancactus
psilocybine – obtained from fungi(„magic mushrooms“) - Psilocybemexicana
Pharmacological effects
- Main effect on mental function:
• Alteration of perception
• Visual, tactile, olphactory and auditory hallucination
• x the person still retains insight that the effect is drug induced
• „bad trip“ (especially in anxious persons)
Mechanism of action
– agonists on 5HT receptors (mainly 5HT2)
Dependence and adverse effects
Fast developement of tolerance
• Aversive rather than reinforcing properties
• Unpredictability of action(danger ofprecipitating mental disorders, attacks of
schizophrenia)
• Unexpected „flash-back“
• > criminal behaviour, suicide attempts
MDMA (ecstasy)
= 3,4-methylenedioxymethamphetamine –central stimulant with mildhallucinogenic effect
Pharmacological effects
- Inhibition of monoamine transporters increased monoamine
concentration and depletion of neuromediators in some parts of brain
- 5-HT psychotomimetic effect
- NA a D euphoria (followed by dysphoria)
Does not lead to dependence
However, it carries serious risks
- Acute hyperthermia(demage of skeletal muscle and renal failure)
- Escess water intake and water retention(ADH release- desorientation,
collaps)
- Heart failure
- After-effects – depression, anxiety, irritability, increase aggression
- Deterious effects on memory and cognitive functions in heavy users
KETAMIN, PHENCYCLIDINE
• Ketamine – disociative anaesthetic – „recreational drug“
• Phencyclidine („angel dust“)- analogue of ketamine
- Feeling of euphoria
- At higher doses desorientation, hallucination, psychotic states
(in experimental animals produce a model of schizophrenia)
- Blockade of NMDA receptor channel
- Combination of ketamine with depressants (alcohol, heroin..) dangerous overdose
OTHER PSYCHOTOMIMETIC DRUGS
• Salvinorin A – hallucinogen contained in Salvia divinorum
- Agonist on κ – receptors
- „herbal ecstasy“, delirium in high doses
• DMT (dimetyltryptamin), DOM (2,5-dimethoxy-4-metamfetamin)–
efect similar to LSD
• Ibogain – in the root bark of iboga shrubs– users reported
reduced desire to také other drugs (cocaine, heroine) –
investigated as potential treatment for drug craving
CANNABINOIDS (MARIJUANA)
• Substances contained in Canabis sativa plant
tetrahydrokanabinol (THC)
• the main active constituent – the most effective psychoactive
component
• Precursors cannabidiol and cannabinol
Abused forms:
• hashish - resinous substance secreted by glands on the leaves and female
inflorescences
• marihuana – dried canabis leaves
Pharmacological effects
- Psychotomimetic and depressant actions
- Euphoria, feeling of relaxation, sharpened sensory awareness(sights, sounds more intense)
- (objective tests: impairment of learning, memory and motor performance, impaired driving ability)
- Analgesic and antiemetic effects, useful in spasticity of Parkinson disease, sclerosis multiplex
• Peripheral autonomic effects (vasodilatation, bronchodilatation, decreased intraocular pressure)
• Cannabinoids are less liable than opiates, nicotine or alcohol to cause dependence, but have long-term psychological effects
nabilon – antiemetic effect (used in anticancer therapy)
rimonabant – selective CB1 antagonist - treatment of obesity
Endocannabinoids
• Anandamide
• 2-arachodinoylglycerol