Lecture 5: Cocaine

Question 1

Pharmacokinetics Of Cocaine

ABSORPTION

Answer 1

• snorted
  1. insufflation
• absorbed through mucous membranes (70% bioavailable)
• dissolution creates HCL –> corrosive to nasal structures (lower pH level)
• onset 3-5 min
• duration 30-40 min

2. inhalation of free-base smoke
   - onset 6-10 sec
   - intense, short duration 5-30 min (feeling of rush)
   - designed to be smoked
   - cocaine HCL pyrolyzes (breaking with fires) before it vapourizes (195 degrees C)
   - cocaine will burst
   - crack vapourizes at 98 degrees C
3. injection
   - onset 10-15 sec
   - duration 10-20 min

Question 2

Pharmacokinetics Of Cocaine

METABOLISM & EXCRETION

Answer 2

• primarily liver CYP3A4
• major metabolite is benzoylecgonine (40% spontaneouly produced by hydroylisi within 4 hours of use
• liver/plasma esterases generate ecgonine methylister
• co-administered with alcohol –> generates cocaethylene metabolite
• mthylecgonidine is by-product of pyrolysis
• detectable in urine up to 4 days after use
• excertion (primarily kidneys)

Question 3

Pharmacokinetics Of Cocaine

SUMMARY (ADME)

Answer 3

DISTRIBUTION
- brain
- kidney
- spleen

ABSORPTION
- inhalation
- injection
- insufflation
- ingestion

METABOLISM
- liver CYP450 ensymes
- liver/plasma esterases 30-50%
- non-enzymatic hydrolysis (40%)
- 12 hr half-life

EXCERETION
- urine –> detectable for 4 days, 2 weeks in chronic users
- sweat
- saliva
- breast milk

Question 4

Acute Effects Of Drug

Answer 4

• stimulating, invigorating
• sympathomimetic (sympathetic nervous system)
• SNS: fight or flight

BRAIN
- euphoria
- arousal
- increased energy
- takes longer to fall asleep

HEART
- increased heart reat and blood pressure
- constricted blood vessels
- promotes blood clots formation

LUNGS
- increased respiratory rate
- dilated bronchi

GI TRACT
-decreased appetite
increased fat breakdown (liver)
- dry mouth
- headache

Question 5

Physiological Effects Of Cocaine

Answer 5

1. Anaesthetic
   - blocks Na channels –> blocks neurotransmission, no pain
   - in the heart –> dysrhythmias
2. excess DA, 5HT, NE, EP result in sympathomimetic effects:
   - increased heart rate, blood pressure
   - anorexia, insomnia, agitation, hyperthermia
3. repetitive, compulsive movements –> basal ganglia
   - influences planning, problem-solving, social behaviours –> PPC
   - extremely rewarding –> NAc
   - high dose can affect medulla –> respiratory and circulatory failure

Question 6

Physiological Mechanisms Of Cocaine

Answer 6

• Blocks transporter activity within synapses
• Prolonged stimulation of post-synaptic nerves
• Aromatic ring and amine group mimic NTs
• Involves DA, 5HT, NE
• DA excess in basal ganglia, PFC, VTA, NAc
• 5HT excess underlies mood, sleep, appetite, temperature
• NE excess underlies sympathomimetic effects
• Enhances VTA sensitivity to Glu and reward

Question 7

Adverse Effects Of Acute Cocaine Use

Answer 7

• Irritability, hostility, anxiety, fear, restlessness
• Formication → delusion of crawling insects under skin
• Psychological events include depression, aggression, paranoia
• Increased acute infections in GI tract → reduced blood flow causes
  tissue to die
• Nosebleeds
• Allergic reactions at injection sites, HIV
• 30-60% of users combine use with alcohol
• Altered metabolism → cocaethylene, a potent
  vasoconstrictor

Question 8

Reinforcing Mechanism Of Cocaine Involves Block Of DA Reuptake

Answer 8

• orange balls (dopamine)
• at the top (presynaptic neuron)
• at the bottom (postsynaptic neuron)
• blue thing attached at the presynatic neuron ( dopamine transporter)

Question 9

Mechanism Of Cocaine Binding To Dopamine Transporter (DAT)

Answer 9

• Cocaine binds same site as dopamine
• Locks transporter in stable
  conformation → inactivates
  transporter
• Exclusive DAT blockers do not
  mimic cocaine effects → not just DA
  involved
• Cardiovascular effects due to block of
  NE (hypertension) and EP (heart rate)
  reuptake
• Mood, appetite → 5HT

Question 10

Cocaine-Induced Mechanisms Of Tolerance

Answer 10

• Reduced euphoria → depleted DA,
  increased DAT efficiency
• Internalization of D1 and D2 receptors
  via rapid mechanisms
• Down-regulated internalization after
  two weeks, might cause D1 upregulation
• Altered opioid-ergic signaling → striatal dynorphin
  expression is induced
• Little or no metabolic tolerance in rats
• Reverse tolerance:
• Increased susceptibility to hyperthermia,
  convulsions, stereotyped movements
• Intermittent use associated with strong behavioural
  sensitization, increased locomotor activity

Question 11

Withdrawal

Answer 11

• Symptoms include depression, anxiety, appetite changes
• Strong drug cue-associated cravings
• Long-term DAT efficiency increases
• May explain common depressive episodes, negative affect
• Relatively mild withdrawal compared to ethanol, sedatives
• ‘Let down’ 30 min after use, exhausted DA circuits
• Severity is dependent on dose and duration
  of use

Question 12

Dependence

Answer 12

• Mild physical
• Intense psychological → hijacked reward pathway and cue
  association
• Most users do not become addicted → anxiety or loss of motor
  control is not fun
• 10-15% of users that snort become addicted
• Progressive self-administration schedule:
• Exponential increase in effort (e.g. pressing a bar 2, 4, 8, 16, 32,
  64, etc.)
• Most drugs, animals will give up
• Chimps will press over 12800 times, some animals will OD
• Animals will forget lifestyle routines and focus on administration

Question 13

Treating Acute Cocaine Intoxication

Answer 13

• Benzos can control agitation, overstimulation
• Decrease BP, heart rate to counteract cardiac
  effects by decreasing NT release
• Nitroglycerine evokes NO production →
  counteract vasoconstrictive effects
• Especially useful to supply heart with oxygen
• Ice bath for cooling body
  temperature
• Experimental treatment with i.v.
  butyrylcholinesterase causes
  rapid elimination of cocaine
• Extended enzyme half-life
  72+ hours

Question 14

Long-term Consequences Of Cocaine Use, Lifestyle, Common Health Risks

Answer 14

• Cardiovascular disease → ¼ of heart attacks in 19-45
  year olds
• Arrhythmias, arrest due to inhibited Na channels
• Constricts vessels, limits blood supply to multiple organs,
  organs start to die
• Psychosis in high dose users, accelerated brain aging
• Rhabdomyolysis breakdown of muscle tissue due to
  hyperthermia → myoglobinuria and kidney failure
• Increased blood coagulability, decreased fibrinolysis →
  increased stroke risk
• User are 14x more likely to experience stroke

Question 15

Long-term Consequences Of Cocaine Use, Lifestyle, Common Health Risks

BRAIN X-RAYS

Answer 15

• reduced D2 expression in the straitum
• decreased brain volume and mass after 10 months of abuse