PowerPoint bemutat

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Psychomotorstimulants
Timár Júlia
2009
timjul_at_pharma.sote.hu
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PSYCHOSTIMULANTS
?
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EFFCECTS
?
?
DA in the brain
hallucination
euphoria is reduced?
?
stimulant effect
dependence
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cocaine
amphetamines
mesolimbic-mesocortical pathway
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transmitting neuron
DA (5-HT, NA) packaged in vesicles
dopaminereceptors
postsynaptic neuron
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Mechanism of action of cocaine
DA endterminals in n. accumbens
vesicles
DAT
dopamine receptors
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Mechanism of action of amphetamines
DA endterminals in n. accumbens
vesicles
amphetamines
DAT
amphetamines
dopamine receptors
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REVERSE TRANSPORT
MAO
AM
DA
Amphetamine(AM)
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EFFECTS of PSYCHOSTIMULANTS
well being euphoria - rash, high
increase of physical abilities
increase of mental capacity (controversial)
effect depends on dose route of
administration first or repeated adminis
tration accompanying circumstances
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DRUGS of ABUSE
TYPE DEPENDENCE POTENTIAL
Stimulants
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Psychic Physical Tolerance Drug
Dependence Morphine
Derivatives
Amphetamine-like () Cocaine () ()
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SELF-ADMINISTRATION
continuousincrease
noincrease
opiods
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AMPHETAMINES
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dextrarotatory form is biologically more active
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CH2 - CH - NH2
Methylenedioxyamphetamine (MDA)
Methylenedioxymetamphetamine(MDMA, ecstasy,
Adam, E, essence)
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EFFECT of AMPHETAMINES

• Increased motor activity
• Euphoria and excitement

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AMPHETAMINE EUPHORIA

• Run
• Rush ( orgasm like reaction sex drive
  is enhanced)

• Subjects become confident, hyperactive,
  talkative (MDMA entactogen)

(military persons, pilots, students - exams
??)
Exhaustion (lack of sleep, food)
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EFFECT of AMPHETAMINES

• Increased motor activity
• Euphoria and excitement

• Anorexia

• With prolonged administration, stereotyped and
  psychotic behaviour

• Tolerance to the stimulant effects develops
  rapidly, though peripheral sympathomimetic
  effects may persist

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In subjects who are
rested, at ease and mentally alert
drowsy, bored or tired
amphetamines produce
alertness euphoria increased vigour mental/physica
l abilities are increased
anxiety irritability
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Therapeutical apply of amphetamines

• narcolepsy

• attention deficit hiperkinetic syndrome

• they used to be used (e.g. dexfenfluramine)
  as appetite- suppressants

Therapeutically used amphetamine derivative is
METHYLPFENIDATE(low abuse potential)
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TOXIC EFFECTS of AMPHETAMINES
Central nervous system agitation convulsions
muscle rigidity hyperthermia sweating dehydrat
ion hallucinations panic dilated pupils coma
Cardiovascular system tachycardia
ventricular arrhythmias hypertension
followed by hypotension spontaneous
bleeding stroke
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TOXIC EFFECTS of AMPHETAMINES
Gastrointestinal system jaundice
hepatomegalyRenal system oliguria
myoglobinuria Laboratory tests metabolic
acidosis hyperkalaemia raised creatinine,
creatine
phosphokinase, impaired liver function tests
hypoglycemia Hematology disseminated
intravascular coagulation (DIC)
(thrombocytopenia, abnormal coagulation
profile, low fibrinogen)
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Treatment of MDMA intoxication
supportive therapy
ventilation, gastric lavage with charcoal
agitation /convulsions diazepam
hypotension fluid therapy, inotropic support
temperature control over 42o C no survival
!!!! cooling blankets, ice packs, infusion of
cold saline etc.
neuromuscular blockade dantrolene (inhibits
Ca release from SR )
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Treatment of MDMA intoxication II
supportive therapy (cont.) metabolic acidosis
precipitating cardiac arrhythmias sodium
bicarbonate DIC with severe bleeding
replacement of clotting factors,
specific therapy ??? selective 5-HT2 receptor
antagonist ketanserin chlormethiazole
attenuates thermogenesis given before MDMA (rat)
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REPEATED AMPHETAMINES
Tolerance can develop to euphoria anorexia hyp
erthermia acute lethal effectsanorexia ?
ketosis ? acidic urine ? increased elimination
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WITHDRAWAL SYMPTOMES

• extreme fatigues
• long, restless sleeping
• marked appetite
• drug seeking behaviour
• depression

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ROUTES of ADMINISTRATIONS
Amphetamine i.v. orally Methamphetamine i.v.
orally inhaled
MDMA orally (generally)
Methamphetamine initial dose 20-40
mgMDMA initial dose 50-100 mg
t1/2 amphetamine 10h
methamphetamine, MDMA 5h
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METABOLISM of MDMA
demethylation by CYP2D6 POOR METABOLISERS
(7-8) risk of toxicity increases CYP2D6 enzyme
function is inhibited by SSRI-s
(fluoxetine, paroxitene etc.)
phenotiazine antipsychotics
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Following repeated MDMA abuse
depression risk of comitting
suicide agressive bahaviour is more
marked than with amphetamine (5-HT-erg
effect?)
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PERINATAL OUTCOME IN INFANTS WHOSE MOTHERS USED
AMPHETAMINE DURING PREGNANCY
Study group
Control group
Perinatal mortality Infant mortality Major
malformations Birthweight lt 2500 g Gestational
age lt 37 weeks Transfer to neonatal unit
5.6 5.8 3 18 20 38
1.04 0.83 1.64 4.6 5.65 10
(Sweden)
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Methamphetamine, MDMA abuse is frequent
together with cannabis (70-80?) benzodiazepin
es (40-50) is rare together with heroin
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(No Transcript)
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McCann UD et al,(1998) Lancet, 352, 1433
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These brain scans show that dopamine receptor
levels are lower in methamphetamine abusers than
in control subjects. High dopamine receptor
levels appear red, whilelow levels appear
yellow/green.
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Decreased DA activity
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Parrott AC, Lasky J (1998) Psychopharmacology,
139, 261
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McCann UD et al, (1999) Psycho-pharmacology,143,
417
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COCA plant
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COCAINE
free base crack by alkalization andextraction
insoluble, very lipophylic
hydrophylic, white powder coke, gold dust,
lady
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COCAINE routes of administration
crack
plasma level ng/ml
chewing
i.v.
sniffing
smoking
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THE INTENSITY AND TIME COURSE OF COCAINE
INTOXICATION
Maximum
iv
smoking - crack
Cocaine high
i.nasal
oral
None
10
20
30
40
50
60
120
Time (min)
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PHARMACOKINETICS of COCAINE
t1/2 50 min
distribution into the brain is very
quick redistribution is also very quick
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METABOLISM of COCAINE I.
Main metabolites benzoilecgonine ecgonine
methylesther
Metabolizing enzyme - cholinesterase
reduced serum cholinesterase activity in ?
foetus ? small children ? pregnant
women ? elder people ? hepatic failure ?
genetic cholinesterase deficiency
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METABOLISM of COCAINE II.
Elimination via kidney detectable for 24-36
hours via sweat detectable for
weeks in the hair detectable for years!
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SPECIAL TOXIC EFFECTS of COCAINE

• i.v.
• endocarditis, hepatitis, AIDS, thrombophlebitis
• intranasal
• rhinitis, septum perforation spontaneous
  pseudomediastine

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COCAINE OVERDOSE
COLLAPSE of CIRCULATION arrhytmia ischaem
ia myocardial infarct seizures
stroke MIGRAINE HYPERTHERMIA
RESPIRATORY DEPRESSION
CENTRAL SYMPTOMS anxiety parnoia fear
of death
POSSIBLE LETHAL OUTCOME within 2-3 hours
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COCAINE OVERDOSE
nose - bleedingheadacheexhaustion/depressionhoa
rsenesscardiovascular problems
SYNDROME of DIAGNOSTIC VALUE
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COCAINE WITHDRAWAL SYMPTOMES

• very marked craving, which gradually decreases
  after a couple of day and than ceases
• exhaustion
• sleepiness
• depression
• decrease of heart rate

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COCAINE ABUSE and PREGNANCY

• birthweight is smaller
• head circumference is smaller
• CNS developmental disorders because of
  foetal vasoconstriction

• withdrawal symptomes of the newborns
• trembling
• sharp crying voice
• sweatening

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THERAPY of COCAINE DEPENDENCE

• blockade of DA receptors (neuroleptics e.g.
  haloperidol)

• blockade of cocaine binding site on DA -
  transporter protein

• replacement therapy ? DA-uptake inhibitors
  (e.g. mazindol)
  DA-agonists (e.g. bromocriptine)
  DA-releasers (e.g. amantadine)

• on the basis of common DA theory buprenorphine,
  naltrexone

• tricyclic antidepressants (at withdrawal)

• symptomatic therapy (e.g. i.v. diazepam
  propranolol)

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31 OF NEW YORK MURDER VICTIMS HAD COCAINE IN
THEIR BODIES
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EFFECT OF A SINGLE COCAINE EXPOSURE ON DOPAMINE
CELLS
indication of long-term potentiation
NIDA NOTES 16/5 (2001)
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Methamphetamine abusers typically take the drug
early in the morning, and take it at 2 - 4 hour
intervals throughout the day
Cocain abusers usually take the drug in the
evening rather than the daytime, and take it
continuously over a period of several hours