14. Drugs of abuse 2 (cocaine & nicotine)

Question 1

where does cocaine come from?

Answer 1

plant-based compound (erythroxylum coca plant)

Question 2

what are the different forms of cocaine and how are they taken?

Answer 2

• paste: 80% cocaine, organic solvent (oral, intranasal)
• cocaine HCl: dissolve leaves in acidic solution (oral, intranasal)
• crack: precipitate cocaine HCl with an alkaline solution (e.g. baking soda) (inhalation)
• freebase: dissolve crack in a non-polar solvent (e.g. ammonia) to purify it (inhalation)

Question 3

compare inhalation, intranasal and IV administration of cocaine

Answer 3

• speed of onset is the same for inhalation and IV
• HOWEVER IV administration is much better for getting a large amount in the blood (100% bioavailability)
• a lot of the drug is lost due to absorption issues in inhalation
• intranasal has a slower speed of onset
• oral administration has the slowest speed of onset

Question 4

why is oral administration of cocaine the slowest?

Answer 4

pKa = 8.7, so if taken via the oral route, cocaine will be ionised in the GIT (acidic environment)

because it is ionised, it is slowly absorbed –> prolonged action

Question 5

describe the metabolism of cocaine

Answer 5

• rapidly metabolised (half life of 20-90mins) by plasma and liver cholinesterases
• 75-90% is broken down into inactive, inert metabolites

Question 6

what are the metabolites of cocaine?

Answer 6

ecgonine methyl esther

benzolyecgonine

Question 7

why is cocaine so addictive?

Answer 7

speed of onset: the effect comes on quickly (powerful behavioural stimulus)

speed of breakdown: powerful, euphoric high very quickly which is also lost very quickly (reinforcing effect)

Question 8

what are the 2 major effects of cocaine?

Answer 8

1. local anaesthetic (high dose): diffuses into cytoplasm (has to be uncharged) –> blocks sodium channels from cytoplasmic side of nerves –> reduces propagation of APs –> suppresses pain
2. reuptake inhibition (low dose): blocks reuptake of dopamine (dopamine transporter) and NA (NA reuptake transporter)

Question 9

what does the dopamine transporter do?

Answer 9

takes dopamine molecules from the synapse and flips it back into the pre-synaptic cell

Question 10

does cocaine influence dopamine affinity or efficacy for the dopamine receptor?

Answer 10

no - cocaine blocks the reuptake protein, affinity and efficacy is related to interactions at the receptor

Question 11

where does cocaine act?

Answer 11

goes straight to the nucleus accumbens to block the dopamine transporter and increase dopamine in the synapse

Question 12

what are the other effects of cocaine?

Answer 12

positive effects (acute use): euphoria, heightened energy, talkative, increased libido, inflated self-esteem

negative effects (chronic use): irritability, anxiety, fear, exhaustion, insomnia, violence, anorexia, delusions

Question 13

why do negative effects occur from cocaine binging?

Answer 13

increased tolerance means some of the euphoric effect is lost after chronic use

reuptake is prevented so dopamine will eventually be metabolised and will not be taken back up into the neurone –> dopamine vesicles reduced –> loss of positive/reinforcing euphoria and gain of negative effects

Question 14

outline the cardiovascular effects associated with cocaine

Answer 14

increased sympathetic output –> increased catecholamines LEADS TO:
- increased HR, contractility, BP –> increased oxygen demand
- coronary
vasoconstriction –> reduced oxygen supply
- platelet activation –> reduced oxygen supply

can cause atherosclerosis, endothelial injury, MI, arrhythmias

Question 15

what are the 2 major CVS problems of cocaine?

Answer 15

1. effects on the sympathetic NS

2. decreased sodium transport creating a local anaesthetic effect

Question 16

what is a common feature of cocaine overdose and why?

Answer 16

seizure

due to vasoconstriction in the brain (reduced blood flow to parts of the brain) + hyperpyrexia (high fever, stimulated by cocaine) –> seizure and epilepsy

Question 17

outline the hyperthermic effects associated with cocaine

Answer 17

cocaine overdose –> increased agitation, increased locomotor activity, increased involuntary muscle contraction –> increased body temperature –> hyperthermia

Question 18

how does cocaine influence sweat production and cutaneous vasodilation?

Answer 18

cocaine inhibits cutaneous vasodilation (because it increases SNS –> increases vasoconstriction)

cocaine enhances sweat production

Question 19

what is in a cigarette?

Answer 19

95% volatile material (N, CO, CO2, benzene, HCN) and 5% particulate matter (alkaloids (nicotine), tar)

Question 20

how is nicotine delivered to the body?

Answer 20

when the cigarette is heated, tar droplets form which nicotine dissolves into

droplets enter the lungs and nicotine diffuses across alveoli

Question 21

describe the dosing of nicotine

Answer 21

• 9-17mg/cigarette
• 1mg/nicotine spray
• 2-4mg/nicotine gum
• 15-22mg/day/nicotine patch

Question 22

compare the effectiveness of nicotine administration (in terms of bioavailability)

Answer 22

• spray: 20-50%
• gum: 50-70%
• cigarettes: least effective
• patch: 70%

Question 23

why do cigarettes have a poor availability?

Answer 23

cigarette smoke is acidic and nicotine has a high pKA of 7.9 so nicotine is heavily ionised in the smoke and therefore poorly absorbed (no buccal absorption)

Question 24

why do people binge on cigarettes?

Answer 24

to constantly replace the peak effect of nicotine to restore the high as cigarettes give a spike in plasma levels of nicotine rather than a constant level

Question 25

describe the pharmacokinetics of nicotine

Answer 25

• 70-80% metabolised in liver by hepatic CYP2A6 to an inactive metabolite
• slower metabolism than cocaine (half life of 1-4 days)
• powerful reinforcing power because the effect is lost quickly

Question 26

how does nicotine act on receptors?

Answer 26

there are nicotinic receptors in the PNS and SNS

nicotine activates the ANS and allows ACh to bind to its active site to open the ion channel and transmit signals from one nerve to the next

Question 27

why is nicotine a euphoriant?

Answer 27

• it is a stimulant so will act directly on the neurone itself to stimulate it
• there are lots of nACh receptors on the cell body of reward dopaminergic neurones
• heavy stimulation leads to dopamine release in the nucleus accumbens –> reward feeling

Question 28

why is long term nicotine use associated with cardiovascular effects?

Answer 28

• has the same effect on the CVS as cocaine (increases platelet activation, coronary vasoconstriction, HR, contractility and BP)
• also worsens lipid profile by increasing free fatty acids, LDL and VLDL contributing to atherosclerosis more

Question 29

what effect does nicotine have on metabolic rate?

Answer 29

increases - associated with weight loss

Question 30

which neurodegenerative disorders does nicotine impact?

Answer 30

• parkinson’s disease

- alzheimer’s disease

Question 31

how does nicotine impact parkinson’s disease?

Answer 31

• long-term nicotine use increases the number of brain cytochromes (CYPs)
• CYPs metabolise neurotoxins
• chronic nicotine use has a positive impact on the disease

Question 32

how does nicotine impact alzheimer’s disease?

Answer 32

• chronic use decreases beta-amyloid toxicity and decreases amyloid precursor protein (APP)
• nicotine has a positive impact on the disease

Question 33

why might caffeine (a stimulant) cause euphoric effects?

Answer 33

• adenosine activates adenosine receptors which decrease the euphoric effect
• adenosine down regulates D1 function and decreases dopamine secretion
• caffeine is an adenosine receptor antagonist
• caffeine increases dopamine release and enhances tissue response to dopamine

Question 34

why is the euphoric effect of caffeine not very obvious?

Answer 34

because of the low dose and because caffeine is usually orally administered