Download Substance abuse

Neuropharmacology of CNS & Substance Abuse
• Story of MPTP (1-methyl-4-phenyl 1,2,3,5tetrahydropyridine)
• Monoamine oxidase (MAO) in astrocytes
• Oxidative phosphorylation
Anatomy of the nervous system
• Neurons
• Interstitial cells
– Astrocytes
– Oligodendrocytes, Neurolemma, Schwan cells
• Myelin Sheaths
• Nodes of Ranvier
• Anterograde, Retrograde, Microtubules
• Motor proteins
• Kinesin, Dynein
• Microglials, phagocytic cells macrophage/monocyte
Morphological considerations
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Nutritional and biochemical aspects
Brain-blood-barrier
Tight junctions, Endothelial
Anoxic or hypoglycemic
The Synapse
• Three elements: Presynaptic, Postsynpatic, Synaptic cleft
• 4 steps: 1. synthesis storage; 2. transmitter release; 3.
receptor activation; 4. neurotransmitter inactivation
Specific neurotransmitter system
• Acetylcholine
– Muscarinic,
– Nicotinic
• Glutamate- excitatory
– AMPA, Kainate, NMDA
• GABA - inhibitory
– Subtype A and B
• Glycine- inhibitory, Spinal cord, strychnine
Substance abuse
• Background
– main types of abused drugs Table
– no insulin or penicillin "junkies"
Tolerance
• diminishing drug effect following repeated administration.
Higher doses are needed to produce the same effect.
• May be pharmacokinetic or pharmacodynamic tolerance
• pharmacokinetic : induction of hepatic metabolic enzymes
e.g. barbiturates;
• pharmacodynamic: alteration at receptor levels e.g.
decrease of GABA receptors followed by increase of
barbiturate administration; morphine and its receptor.
• Tolerance may be developed only one effect of the drug
but not the others; e.g. in opiates, euphoric and analgesic
effects are tolerated but the respiratory depression is not.
Cross-tolerance
Cross-tolerance means that individuals tolerant to one drug
will be tolerant to other drugs in the same class, but not to
drugs in other class.
Drug dependence
• signs and symptoms upon withdrawal when drug levels fall
drug dependence with opiates
1. opiates inhibits the firing of locus ceruleus (LC)
neurons by interacting with m receptors.
2. long term opiate administration causes molecular
adaptations in the signaling properties of neurons.
3. decrease signaling; without decreasing the numbers or
affinity of the receptors.
4. cAMP cascade is up-regulated, phosphorylation of a
slow depolarizing Na+ channel, neuronal excitability.
5. hyper-excitable state becomes manifested when
withdrawn
• withdrawal symptoms vary with drugs. barbiturates,
alcohol, possible death
• cross-dependence : drug A that show cross-tolerance with
drug B of the same class also support the dependence of B .
Caffeine
• competitive antagoinst of adenosine receptors
• sedative
• caffeine is an addicting drug because it shows
reinforcement and its withdrawal induces symptoms:
headache, drowsiness, fatigue, decreased performance,
depression
Methadone maintenance
• opiate agonist, analgesic, to replace the addict's heroine
• maintenance basis (same dose, chronic use), withdrawal
basis (gradually reducing dose, 1-6 months)
• cocaine,
– HCl, freebase, crack, 1-2 min peak CNS effects
– dopamine receptor agonists
Addiction Liability
• animal behavior paradigm self-administer
• Table of Addiction risk of major psychoactive drugs
• reward pathway center, dopaminergic neurons ventral
tegmental area; forebrain,
• euphoria reinforcement cycle
War on drugs
• a perceived threat, moral principle
• Table. Number of yearly drug-related deaths
• Tobacco, Alcohol >> Cocaine, Heroine, Aspirin
Descriminalization
• Netherlands, soft and hard drugs coffee shop 4.6% use
cannabis vs 4.8% in U.S.
Drugs in Sports
• Background
– not drug abuse but illicit use of banned substances
• History
– Scandinavian warriors, muscarine, psychoactive
alkaloids
– 1800s amphetamine, strychnine and ephedrine
commercially available
– IOC ban (1) substances of selected groups; (2) doping
methods.
– rationales : clearly enhanced performance, medical
safety, social acceptability
Stimulants
• amphetamine, cocaine and strychnine
• delay onset of fatigue
• caffeine, phenylpropanolamine, ephedrine
• problem for legitimate health medication
– Rick DeMont episode
• alternatives salbutamol terbutalin by inhaler only
Narcotics
• morphine, pain killers, alternative
• OTC cold cough remedies contain dextromethorphan
Anabolic agents
• anabolic androgenic steroids (AAS) testosterone and its
derivatives
• treatment bone marrow failure anemias
• moderately high dose  gain 13 lbs pure muscle
• side effects females masculinization low vocie
• use of AAS in international sports competitions
• urine test testosterone:epitestosterone T:E ratio
 b-2 agonist asthma relief clenbuterol
• livestock industry growth promote
– drug treated meat
• Alekey Petrov story
Diuretics
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urine excretion conceal evidence of the misuse of drugs
rapid weight loss
weight classes boxing wrestling
masking agents probenecid prevent secretion of AAS
epitestosterone T:E ratio
absolute level : no more than 200 ng/ml
Miscellaneous drugs
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b-blockers,  blood pressure
cardiac output, hypertension, cardiac arrythmia, angina
shooting archery
chorionic gonadotropin  androgenic steorids
testosterone 
corticotropin (adrenal stimulatory trophic hormone)
corticosteroids
• erythropoetin (EPO) red blood cell production blood
samples
Blood doping
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oxygen-carrying capacity
technique
withdrawing 1 liter blood, store frozen 9-12 weeks
hemoglobin return, reintroduce
搖頭丸
俗稱或快樂丸的毒品事實上屬於安非他命的衍生物，
英文叫作MDMA(3,4-methylenedioxy-methamphetamine)或Ecstasy.
搖頭丸是在1914年，由德國默克(E. Merk)公司合成為減肥藥用途，
後來發現此藥最主要作用與興奮劑及迷幻效藥物類似。
因此，未能上市。直到了1980年，雖然FDA未能通過，
卻有不少此類藥物，被用來作精神治療的輔助劑。
自從1983年起，搖頭丸逐漸的被美國大學生廣泛的使用。
美國政府乃在1985年，加以立法管制。
國內自1990年起安非他命廣泛流行後，
最近幾年來在舞廳及，才開始流行搖頭丸。
事實上市面上販售的搖頭丸有些不只含有MDMA的成份，
更有添潻加甲基安非他命及安非他命、或咖啡因等成份‧會增加其毒性作用
。
Flunitrazepam (FM2)
commonly abused benzodiazepines drugs such as Flunitrazepam (FM2),
Diazepam (Valium), Triazolam (Halcion), Lorazepam, and Oxazepam
RU468
abortion drug, anti-progesterone effect
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• 白板:
• 來源：屬禁用之安眠鎮靜類製劑。
• 性狀：主成分為Methaqualone(Mandrax)
甲口奎酮，白色結晶性粉末製成錠劑。