Pharmacology 14 - Drugs of Abuse 2

Question 1

How does cocaine lead to MI?

Answer 1

• Reduced noradrenaline reuptake (resulting in coronary vasoconstriction, heart rate, and blood pressure increasing, increased platelet activation, contributed to atherosclerosis and ischaemia)
• Increases sympathetic output
• Causes inflammation and decreased sodium ion transport, which contributes to endothelial injury and decreases left ventricular function
• Arrhythmias and sudden death

Question 2

How does cocaine cause hyperthermia?

Answer 2

• Seen in cocaine overdose
• Enhances locomotive activity, agitation, and involuntary muscle contraction which all generate heat so the body temperature increases, if in a hot environment there will be hyperthermia
• Cocaine elevates the threshold for cutaneous vasodilation and sweating
• Inhibits cutaneous vasoconstriction, and enhances sweating slightly

Question 3

Describe dosing of nicotine

Answer 3

• Plant based alkaloid. When heated, there is particulate matter (5% alkaloids and tar) and volatile matter (95% containing nitrogen, carbon monoxide)
• Nicotine spray – 1mg
• Nicotine Gum – 2-4mg
• Nicotine
  Cigarettes – 9-17mg nicotine
• Nicotine Patch – 15-22mg/day

Question 4

Describe the mechanism of nicotine action causing euphoria

Answer 4

• Binds to nicotinic receptors on the dopaminergic neuron in the ventral tegmental area to stimulate the nerve
• Causes release of dopamine at the nucleus accumbens

Question 5

How does nicotine affect cardiovascular health?

Answer 5

• Increases free fatty acids, LDL and VLDL
• Increases atherosclerosis
• Increases catecholamine release via ganglionic receptors, causing platelet activation, coronary vasoconstriction and increased HR and blood pressure
• Promotes myocardial ischaemia by decreasing oxygen supply to myocardial tissue and increasing myocardial demand

Question 6

What is the effect of nicotine on appetite?

Answer 6

• Increases metabolic rate, which generally prevents weight gain
• When chronic smokers stop smoking, they generally put on weight

Question 7

How does smoking affect parkinsons and alzheimers?

Answer 7

• Parkinsons - increases brain cytochrome P450s which increases the brains ability to break down toxins (neurotoxins)
• Alzheimers - Decreases B-amyloid toxicity and decreases amyloid precursor protein (which are the main contributers to alzheimers)

Question 8

How does caffiene cause euphoria?

Answer 8

• Adenosine binds to adenosine receptors at the dopaminergic neurone and nucleus accumbens, which reduces euphoria
• Caffeine and has inhibitory effect causing increased dopamine release and effect

Question 9

List the effects of cocaine

Answer 9

• Euphoria and dysphoria, energy, sleep disturbance, talkativeness, increased libido, anorexia
• Irritability, insomnia, incoherent speech, violence, delusions

Question 10

List formulations of cocaine

Answer 10

• From erythroxylum coca (leaves contain 0.6-1.8%)
• Paste 80% cocaine and cocaine HCl (dissolved in acid solution) are taken via IV, oral or intranasal route
• Crack (precipitated with alkaline solution) and freebase (crack dissolved in non-polar solvent) taken via inhalation

Question 11

Describe administration of cocaine

Answer 11

• IV 100% bioavailable
• Inhaled speed on onset is fast, but there is low bioavailability (the smoke is acidic, therefore remains ionised due to high pKa. Still diffuses over the alveoli)
• Oral cocaine ionised in stomach (acidic) and poorly absorbed. Cocaine has a high pKa.

Question 12

Describe metabolism of cocaine

Answer 12

• Rapidly metabolised into 75-90% ecgonine methyl ester benzoylecgonine whic are inactive
• Half life 20-90 minutes
• Metabolised via plasma/liver cholinesterases

Question 13

Why is cocaine so addictive?

Answer 13

• Rapid onset

- Short half life (20-90 minutes)

Question 14

How does cocaine act as a local anaesthetic?

Answer 14

• Blocks sodium channels
• Stops sodium influx, disrupting action potentials
• It is better if the cocaine enters the channel from inside the cell (diffuse across the nerve and access the channel from beneath).
• Cocaine has a pKa of 8.7. pH outside the cell is 7.4, and inside is 7.
• Therefore pH outside the cell is closer to pKa so the cell is more unionised and will effectively enter the cell. In the cell it becomes more charged, and less will diffuse out of the cell.
• Inside the cell it is more active when charged, and interacts with the sodium channel better

Question 15

List the effects of cocaine

Answer 15

• Local anaesthetic (higher dose)
• Reuptake inhibition (lower dose)
• Euphoria
• Mild-moderate effects are positive/reinforcing (heightened energy, confidence, anger)
• Severe effects are negative/stereotypic (irritability, hostility, extreme exhaustion, compulsive motor effects, incoherent speech)
• MI
• Hyperthermia

Question 16

How does cocaine affect reuptake of neurotransmitters?

Answer 16

• Blocks monoamine reuptake (noradrenaline, serotonin, and dopamine)
• Therefore it will increase the concentration of the neurotransmitter in the synaptic cleft
• Will not affect affinity or efficacy

Question 17

How does cocaine cause euphoria?

Answer 17

• Blocks dopamine transporters, which reuptake dopamine from the synaptic cleft in the nucleus accumbens
• Therefore, dopamine will build up in the synapse and have a more powerful euphoric effect

Question 18

Describe bioavailability of nicotine

Answer 18

• Patch is most effective (70%), nicotine is lipid soluble
• Cigarette 20% (pKa 7.9. Cigarette smoke is acidic so no buccal absorption)
• Nicotine gum 50-70% (absorption across mucuous membranes of the mouth)
• Nicotine spray 20-50%

Question 19

Describe metabolism of nicotine

Answer 19

• Metabolised to cotinine, a inactive metabolite, via hepatic CYP2A6 (70-80%)
• Half life 1-4 hours
• Therefore does not last long in the blood