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PH3501- Neuropharmacology > Lec 4- Drugs of abuse (2) > Flashcards

Lec 4- Drugs of abuse (2) Flashcards

1
Q

Different rewards and where they act on the mesolimbic reward system

A
  • Opioids- switches of GABA inhibitory neurones=> increase release of DA from VTA = reward
  • Alcohol- very similar to opioids effect
  • Psychostimulant- act directly on the VTA= directly increase the release of DA
    *
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2
Q

Psychostimulants- Cocaine

A
  • Pharmacology: Structurally related to atropine- both plant alkaloids
  • Crack is water-soluble cocaine without HCL which is removed using bicarbonate and water so that it is smokable
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3
Q

Cocaine mechanism of action

A
  • Blocks CNS DA transporter (DAT)- increases ambient DA in NAc by preventing its reuptake
  • Also blocks 5-HT and NA reuptake, but with lower affinity- However mostly acts through DA
  • Produces rapid tolerance, long-term sensitization
  • Withdrawal symptoms- dysphoria (‘crash’) depression, intense anxiety, psychological craving
  • No physiological dependence
  • Toxicity- nasal septum damage, cardiac/blood pressure problems
    • Rats will self-administer until death through starvation
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4
Q

Amphetamine

A
  • Similar to NA
  • More lipid soluble than catecholamine= brain penetrant
  • Methamphetamine (crystal, ICE, Speed)
  • AMP and METH block DAT AND cause release directly by displacing DA from vesicles in the synaptic terminal, same for NA and weakly 5-HT
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5
Q

Amphetamine mechanism of action

A
  • Release
  • Re-uptake
  • DAT block
  • DA re-uptake blocked
  • DA displaced from pre-synaptic terminal
  • Both of this mechanism makes this a very potent drug
  • Same mechanism as cocaine plus another
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6
Q

Amphetamine and methamphetamine

Pharmacology and toxicity

A
  • Pharmacology
    • Decongestant (Benzedrine, now propylhexedrine)
    • Anorectic (sliming drug since the 1950’s)
    • Pro-vigilant (Narcolepsy)
    • Tolerance rapid; sensitization is slower but potent
    • Psychological dependence similar to cocaine
    • Difficult to overdose (sedate with diazepam)
  • Toxicity
    • Chronic use causes paranoid psychosis
    • Amphetamine-specific necrotizing arteritis (brain haemorrhage, kidney failure)
    • Lead poisoning
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7
Q

Amphetamine alters brain structures

A

Terry E. Robinson (1997-2003)

  • Chronic amphetamine administration in rats
  • Golgi silver impregnation of neurones
  • Looking at number and structure of dendritic spines (synaptic connections)
  • Spines where excitatory synapses form on dendrite
  • Changes in spine number associated with synaptic plasticity, alterations in neuronal function- Spines are far greater, more excitatory connections leading to greater reinforcement of the drug
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8
Q

Crystal meth

A
  • Rapidly expanding use (US/UK)
  • Easy to make at home using OTC cold remedies containing ephedrine or pseudoephedrine
  • Other reactants commonly used
    • Isopropyl alcohol; Toluene; Ether; Sulphuric acid; Red phosphorus; Table salt; Iodine; Lithium; Anhydrous ammonia; NaOH: Pseudoephedrine; Acetone; Cat litter
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9
Q

Crystal meth- why so popular

A
  • Very powerful high, long duration (8-24 hrs)
  • Behavioural disinhibition
  • Immensely addictive
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10
Q

Crystal meth- Why so dangerous

A
  • Long duration high (2-3 days) means poor personal hygiene
  • Behavioural disinhibition leads to risk of AIDS/other STD’s
  • High risk of psychosis/delusions (formication) rages
  • Powerful sensitizing effects mean relapse into psychosis very likely
  • Destructive effects in all organ systems
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11
Q

Meth mites (formication

A
  • Meth raises core temperature
  • Increased sweating and dehydration
  • Loss of skin oils
  • PLUS- powerful tactile delusion due to meth use
  • Leads to sensation of insects crawling under the skin
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12
Q

MDMA

A
  • Methylenedioxymethamphetamine (MDMA)
  • Pharmacology
    • Club drug- euphoric, emphatic- designer drug
    • Blocks 5-HT (serotonin) transporter
    • Also causes 5-HT transporter to work in reverse
    • Result- much more ambient 5-HT
  • Toxicity
    • Short term: 5-HT depletion- dysphoria depression; severe acute hyperthermia
    • Long-term: pre-synaptic degeneration, chronic depression, emery and cognitive impairment
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13
Q

MDMA- mechanism of action

A
  • Similar to methamphetamine
  • Receptor= 5HTT
  • Neurotransmitter= 5-HT
  • 5-HT transporter blocked by MDMA and causes the reversal of the pump
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14
Q

Methylphenidate

A
  • Ritalin- used in children with ADHD
  • Weak DA, NA uptake inhibitor
  • No effect on 5-HT
  • Much more effective on mental activity compared to motor activity
  • Potential for abuse due to large increase in availability
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15
Q

Nicotine

Pharmacology

High or low dose

A

Pharmacology

  • Low dose (associated with smoking)
    • Increased alertnessFacilitation of memory and attention
    • Reduced appetite
    • Tremor, muscle relaxation
    • Nausea/ increased respiration
    • Tachycardia/ HTN/ Increased GI motility
  • High dose
    • Depolarizing blockade of neuromuscular junction and autonomic ganglia
    • Can cause death by cardiovascular collapse and respiratory failure
    • Treatment: gastric lavage + general supporting measures
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16
Q

Nicotine- mechanism

A
  • Increase DA release in NAc, increased NAc GABA output to VTA
  • Acts pre-synaptically to increase DA release, postsynaptically to increase DA neurone firing
  • Acts only at nAChR containing Beta2 subunit
  • Also excites cholinergic interneurons in NAc into burst-firing mode- the important component of addiction
  • Potent because it has dual action as it acts at both ends of the VTA cell= cell body and NAc synapse
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17
Q

Addiction therapy

A
  • Nictine patches
  • Low dose bupropion, also called zyba, wellbutrin
  • Weak DA, NE, 5-HT uptake blocker with novel structure
  • Chinese smokers metabolise nicotine slower = less to smoke= less likely to die
    • New research indicatres they have lower levels of cytochrome P450, CYP2A6 isozyme
    • Block CYP2A6 in smokers
18
Q

Depressants

A
  • Depressants include
    • Alcohol: ethyl alcohol
    • Barbiturates: pentobarbital, secobarbital
    • Non-barbituates sedative-hypnotics: Chloral hydrate
    • Anxiolytics: benzodiazepines (diazepam)
  • All act to depress the CNS
    • Lethal combination due to additive action
    • Often highly addictive with severe, protracted withdrawal
19
Q

Alcohol

Pharmacology and toxicity

A
  • Pharmacology
    • Highly soluble crosses BBB with ease
    • Suppresses REM sleep
    • Produces physical dependence rapidly
      • Hangover: EtOH => acetaldehyde, which is stimulant
    • Full withdrawal syndrome is Delerium Tremens
      • Rebound REM sleep leading to hallucinations (esp zoopsia)
      • Rebound hyperexcitability due to loss of tonic GABA enhancement can cause seizures
  • Toxicology
    • Hepatic cirrhosis, alcoholic hepatitis, renal damage, oral & throat cancer
    • Korsakoff’s syndrome- caused by the lack of thiamine (vitB1), symptoms- anterograde amnesia, dementia
20
Q

Alcohol- mechanism of action

A
  • Ion channels
    • NMDA receptor- allosteric inhibitor, Increase NMDAR over time leading to physical dependence withdrawal
    • GABAA receptor- allosteric facilitator, causes tolerance
    • 5-HT2/3 receptor- positive modulator, sedative, antianxiety, euphoric effects
    • L-type Ca2+ channel- allosteric inhibitor
    • nAChR0 positive modulator
    • Enhances A2R activity- synergistic with D1R
    • All of the above help to increase NAc DA activity
  • Cross-tolerance with cannabis- enhances the effects of n-arachidonoyl ethanolamide, an agonist at CB1R increases its synthesis
21
Q

Barbiturates

A

Pharmacology

  • Used as hypnotic and sedative e.g. surgery
  • Synthesised by Hoffman
  • Potent CNS depressant will completely suppress respiration through inhibition of brain respiratory centres
  • Narrow therapeutic window- toxic at only x10 hypnotic dose: hence replaced by benzodiazepines
  • Cheap- used still veterinary ssurgery
  • Physical dependence develops slowly
  • Withdrawal symptoms include anxiety, vomiting, hyperthermia, seizures
22
Q

Barbiturates- mechanism of action

A
  • Act at GABA, receptor channels- B-1 subunits
  • Prolongs GABA opening of Cl- channel- more Cl- passed
    *
23
Q

Barbiturates- use and abuse

A
  • Phenobarbital- long half life(>100 hr); anticonvulsant (status epilepticus) ‘purple hearts’
  • Pentobarbital- Intermediate half-life (15-50 hrs); pre-op sedation ‘yellow jackets’
  • Amobarbital- short half life (<3 hrs); anaesthesia induction
  • All may produce feelings of euphoria/wellbeing, may release DA through Disinhibition
24
Q

Benzodiazepines- pharmacology

A
  • Used as anxiolytics and sedatives (sleeping pills) also the treatment for depression in 1950-60’s- mothers litter helper, treatment for stress or situational depression (e.g. bereavement)
  • 1980’s, 1990’s major problem with addicted patients
  • Abuse may enhance ‘high’ from other drugs
  • Shallow dose-response curve, hard to OD
  • Tolerance develops rapidly, useless as sleeping pulls after 2 weeks, useless as anxiolytic within 3 months
  • Withdrawal after prolonged abused induces anxiety nausea, insomnia
  • Injection of melted temazepam caplets (jellies) cause of significant limb amputation in Scotland (jelly-like NZ solidify in the blood vessel)
25
Q

BDZ- mechanism of action

A
  • Bind to an a-subunit of GABAA receptor
  • Increase frequency of opening of channel, not duration, hence more GABA activity= CNS depression
  • May release DA through disinhibition
  • Commonly used BDZ
    • Midazolam- short-acting(1-3h); brief sedation for minor surgery
    • Triazolam- Short-acting(2-3h); anxiolytic
    • Temazepam- inter acting (10-17h); anxiolytic
    • Lorazepam- inter acting (17-20h); anxiolytic and sedation
    • Diazepam- long-acting(30-60h) anxiolytic and sedation
    • All of the above used as hypnotics
26
Q

Flunitrazepam

A
  • Also called Rohypnol
  • A special case: abused in order to sedate others- date rape drug
  • Produces anterograde amnesia- a condition in which events that occured while under the influence of the drug are not remembered
  • Current Hoffman-La Roche formulae: 0.5mg and 1mg oblong tablet, as well a 1 mg/mLinjectable solution
  • 1mg tablet being phased out, and dye added to other forms to help prevent date rape
27
Q

Opiates

A
  • Narcotics- from the Greek Narkoun to make numb
  • Opium resin from opium poppies, used since ancient times
  • Opium resin contains: morphine, codeine, noscapine, papaverine and thebaine
  • All but thebaine analgesic, but thebaine v.useful in making synthetic opioids
  • Heroin first synthesised by Hoffman 1898, tested on sticklebacks, and on his workers, who said it made them feel ‘heroic’ hence the name
  • Heroin- the sedative for coughs: opiates are antitussive
28
Q

Opiates- common uses

A
  • Morphine- analgesia (terminal cancer, visceral pain)
  • Diamorphine (heroin)- analgesia (as morphine)
  • Buprenorphine- similar to morphine
  • Methadone (management of heroin withdrawal)
  • Codeine, dihydrocodeine- weak opiates, antitussive
  • Meperidine- anaesthesia pre-med
  • Fentanyl- transdermal patches for intractable pain
  • Tramadol- obstetric analgesia (less respiratory depression)
  • Meptazinol- mixed agonist/antagonist (no withdrawal or dependence)
  • Dextropropoxyphene- mild analgesic (+ paracetamol= co-proxamol)
  • Carfentanyl (10,000 x stronger than morphine)- wildnil
29
Q

Opiate-Pharmacology and toxicity

A

Pharmacology

  • Desirable effects: euphoria, sedation, relief of anxiety, analgesia- subjective effects include limb heaviness, lethargy, warmth
  • Undesirable effects: constipation, nausea
  • Tolerance- except to constipation
  • Acute withdrawal severe- ‘cold turkey’, sweating, aching, nausea, vomiting, treated with clonidine

Toxicity

  • Respiratory depression- OD
  • Heroin lung (oedema)
  • Venous collapse
30
Q

Opiates- mechanism of action

A
  • Brain produces endorphins and enkephalins- natural opioids
  • Opiates act at opioid receptors
    • u-‘mu’ mediate euphoria, dependence, sedation, central + spinal analgesia
    • k-‘kappa’ mediate spinal analgesia, dysphoria, miosis
    • delta- spinal analgesia, respiratory depression
  • Opiates produce massive DA release in NAc through inhibition of GABA release onto cells in VTA- Disinhibition
  • Heroin user feels ‘rush’ as DA released
31
Q

Opiates- chronic effects

A
32
Q

Opiates- fentanyl

A
  • 1000x more potent than morphine
  • Used in humans as transdermal patch
  • Abuse: oral transmucosal use of transdermal fentanyl
33
Q

Opiates- carfentanyl

A
  • 10,000 x more potent than morphine
  • Lethal in humans
  • Used to sedate elephants, tigers, rhino etc
  • Moscow theatre seige
34
Q

Krokodil

A
  • Desomorphine, dihydrodesoxymorphine, krokodil
  • Potent (10x analgesic effect of morphine)
  • Super short half-life
  • Massive high with a short duration
  • Toxicity- scaling, necrosis, gangrene, massive reduction in lifespan- 2-3 years
35
Q

Depressants- GHB (gamma hydroxybutyrate)

A
  • Has taken over Rohypnol as date rape drug of choice
  • Pharmacology
    • If a fatty acid derivative of GABA, endogenous- there is a GHB receptor in the CNS
    • Activates GABABRs on presynaptic terminals to reduce GABA and glutamate release
    • Euphoric, sedative, anxiolytic
    • See slow-wave discharges in the brain similar to absence epilepsy
    • Used to treat alcoholic withdrawal
  • Toxicology
    • Tolerance, dependence develop, OD = coma + death
    • Withdrawal symptoms similar to EtOH
36
Q

GHB- mechanism of action

A
  • Acts at GHBR- a GPCR
  • Makes GABA if [GHB} high enough (b): GABA then activates GABABR
  • Acts at GABABR at abuse levels (c)
  • Depresses Glu, GABA and DA release
37
Q

Psychotomimetics

A
  • Mind-altering agents such as LSD, cannabis, PCP and mushrooms cause hallucinations
  • Known since antiuity- involved Shamanic rituals
  • 1960s- psychedella
38
Q

LSD

A
  • Lysergic Acid Diethylamide
  • Indoleamine, as are psilocybin (mushrooms), ibogaine, dimethyltryptamine and most importantly is based on 5-HT
39
Q

LSD

A

Pharmacology

  • Made by Dr Hoffman
  • Acts as partial agonist at 5-HT receptors, but also at NA and DA receptors to some extent- Reduces 5-HT release
  • Raphe activating system (5-HT) critical for action, NAc for DA effects
  • Taking LSD mimics dream-state brain biochemistry (low 5-HT drive, higher cholinergic activity) in a hyper-aroused individual
  • Causes auditory and visual illusions, synaesthesia

Toxicity

  • Short-term: bad trip- dream state amygdala activation= lots of anxiety, LSD experience depends on moo, Anxiety + fear= Horrific hallucinations
  • Long term: Psychosis
40
Q

Phencyclidine (PCP) and Ketamine

A

Pharmacology

  • Club drugs smoked as Angel dust
  • Dissociative anaesthetic, similar to ketamine ‘Special K’
  • Inhibits 5-HT and NA re-uptake
  • Inhibits NMDA glutamate receptors

Toxicity

  • Short term: K-hole, very bad hallucinations, frequently involving visions of own death
  • Long-term: Brain damage, PCP vacuolated neurones, induces apoptosis (neuronal suicide) genes
  • Severe, potential irreversible psychosis
41
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42
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PH3501- Neuropharmacology (28 decks)

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