Drugs of Abuse: Cocaine and Nicotine

Question 1

what is the plant for cocaine?

Answer 1

Erythroxylum coca

0.6-1.8% cocaine

Question 2

what are the forms of cocaine?

Answer 2

o Oral, IV, intranasal:
“Paste” – 80% cocaine (organic solvent).
“Cocaine HCl” – dissolved in acidic solution.

o Inhalational: these are the more potent ones
“Crack” – precipitated with alkaline solution (e.g. baking soda).
“Freebase” – dissolved in a non-polar solvent (e.g. ammonia + ether).

Question 3

which forms of cocaine are purer and therefore stronger?

Answer 3

crack and freebase

Question 4

which form of administration has the fastest onset? which have the slowest?

Answer 4

IV and inhalation have fast onset (short-lasting)

smoking, nasal and oral have slow onset

Question 5

why does oral intake of cocaine have a slower onset?

Answer 5

pKa of cocaine= 8.7, pH is lower in the GIT so cocaine is ionised (charged)
this means slower absorption and therefore prolonged action

Question 6

what are the two metabolites created by cocaine metabolism?

Answer 6

75-90% of cocaine is rapidly metabolised into:
	Ecogonine methyl ester.
	Benzoylecgonine.
these are inactive metabolites
by plasma cholinesterases

Question 7

what is the half life of cocaine?

Answer 7

20-90 minutes

Question 8

what carry out the metabolism of cocaine?

Answer 8

plasma (in the blood) and liver cholinesterases

Question 9

why does the metabolism of cocaine make it addictive?

Answer 9

the rapid metabolism of cocaine means the euphoria is very short lived with a fast onset of euphoria.

Crack is considered one of the most addictive substances

Question 10

what are the 2 major effects of cocaine?

Answer 10

• euphoria (re-uptake inhibition )

- local anaesthetic (sodium blockage)

Question 11

how does cocaine act as a local anaesthetic?

Answer 11

at higher doses, cocaine in an ionised form blocks the sodium channel from the inside (having entered via the lipid membrane in unionised form)
[remember the hydrophilic and hydrophobic pathways of local anaesthetics. Cocaine is an ester]

the blockage of the sodium channel prevent sodium influx and therefore prevents AP conduction

Question 12

how does cocaine inhibit reuptake of monoamines like NA, DA and 5-HT?

Answer 12

cocaine acts as a MAO-A re-uptake inhibitor (uptake 1)
this does not change the efficacy or affinity of dopamine to the receptors, there is just an increase in dopamine in the cleft

Question 13

how does cocaine cause euphoria?

Answer 13

by preventing the reuptake of dopamine, dopamine remains in the cleft to the NAcc for continued stimulation.

Question 14

what are the differences in acute and chronic use of cocaine?

Answer 14

There are initially positively reinforcing effects such as mood amplification and heightened energy
chronic, high-dose use exhibit severe, negative/stereotypic effects such as total insomnia, decreased libido, irritability.

Question 15

how does cocaine use lead to an MI?

Answer 15

• increased catecholamines and increased sympathetic drive on the heart (HR , BP increase)
• increased oxygen demand on the heart
• vasoconstriction reduces O2 supply to the heart
• platelet activation to atherosclerosis
• myocardium ischaemia leads to infarction

most of these effects are due to the increase in noradrenaline due to reuptake inhibition by cocaine

Question 16

how does cocaine promote thrombosis?

Answer 16

Cocaine promotes thrombosis by activating platelets, increasing platelet aggregation

Question 17

how does cocaine cause vasoconstriction?

Answer 17

cocaine stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principal vasodilator produced by endothelial cells

Question 18

how does cocaine cause hyperthermia?

Answer 18

cocaine overdose causes increases locomotor activity, agitation and involuntary muscle contractions.
These all increase body temperature and leads to hyperthermia in a hot environment aided by cutaneous vasodilation, increased sweat production for heat dissipation.

[cocaine increases motor activity and risk of epilepsy]

Question 19

what is a CNS effect of cocaine?

Answer 19

vasoconstriction causes hyper-pyrexia and then epilepsy

at high dose cocaine causes CNS depression

Question 20

what is the plant for nicotine?

Answer 20

nicotana tabacum

Question 21

what are the two major product of cigarettes?

Answer 21

95% volatile substances e.g. N2, CO/CO2, benzene, HCN.

5% particulates e.g. alkaloids, nicotine and tar

nicotine itself diffuses out of the tar droplets in the lungs when deposited

Question 22

what are the different types of nicotine dosage?

Answer 22

o Nicotine spray – 1mg. 20-50% effective.
o Nicotine gum – 2-4mg. 50-70% effective.
o Cigarettes – 9-17mg. 20% effective.
o Nicotine patch – 15-22mg/day. 70% effective.

Question 23

why is there no buccal absorption of nicotine from cigarettes?

Answer 23

pKa of 7.9, cigarette smoke is acidic

absorption in the alveoli however is independent of pH

Question 24

what leads to nicotine addiction?

Answer 24

short lasting action and a fast reduction in plasma concentration of nicotine

i.e. rapid onset but short duration of action

Question 25

what is the half life of nicotine?

Answer 25

1-4 hours

Question 26

how is nicotine metabolised?

Answer 26

Hepatic CYP 2A6 metabolises 70-80% of nicotine into cotinine (inactive and rapidly cleared)

Question 27

where does nicotine bind and what effect does this have?

Answer 27

binds to nicotinic receptors and stimulates Na+ transport

Question 28

what are the molecular effects in the CVS by nicotine?

Answer 28

Stimulation of the nAChRs leads to a SNS activation (CNS & adrenals) with increased catecholamines: - Increased – HR, SV (tachycardia, inceeased CO) - Vasoconstriction of skin arterioles. - Vasoconstriction of coronary arterioles, skeletal muscle arterioles.

Question 29

what effect does nicotine have on fats and cholesterol?

Answer 29

Increased lipolysis, FFAs, VLDLs, decreased HDL increased free fatty acids contributes to atherosclerosis but its a slower build up compared to cocaine

Question 30

what effect does nicotine have on vasodilators and vasoconstrictors?

Answer 30

- Increased TXA2 (--> platelet activity) | - reduced NO.

Question 31

how does nicotine cause euphoria?

Answer 31

nAChRs are found on the soma of the dopamine nuclei in the VTA. Stimulation of these receptors stimulates DA release in the NAcc.

Question 32

what effect does smoking have on metabolism and what is the effect of stopping smoking?

Answer 32

Nicotine leads to an increase in metabolic rate (and decreased appetite) - people who smoke are on average 4 kg lighter than non-smokers - stopping smoking can lead to weight gain as you no longer have a faster metabolism

Question 33

how does nicotine have protective effects against neurodegenerative disorders?

Answer 33

o Parkinson’s disease – increases brain CYPs (neurotoxin enzymes) --> increased breakdown of neurotoxins. o Alzheimer’s disease – decreases beta-amyloid toxicity AND decreases amyloid precursor protein (APP)

Question 34

what is the effect of caffeine in the reward pathway?

Answer 34

Interferes with adenosine binding to the A1 receptor on the VTA neurone and neurone with dopamine receptors. Caffeine blocks the action of adenosine (adenosine antagonist)

Question 35

metabolism of nicotine

Answer 35

CYP2A6 in the liver nicotine--> cotinine

Question 36

how is nicotine excreted?

Answer 36

urine and saliva

Question 37

what are the effects of nicotine? what risk due these effects combined increase?

Answer 37

- increased sympathetic activity - increased vasoconstriction of coronary arteries - promotion of atherosclerosis - increased TXA2 therefore increased platelet activity all of these combined lead to an increased risk of CVD

Question 38

why is nicotine addictive?

Answer 38

rapid onset of effects but short lasting (distribution)

Question 39

what is cocaine? | what is the mechanism of action of cocaine i.e. target?

Answer 39

1) monoamine transporter blocker - targets the uptake 1 transporter on the presynaptic membrane of the Nucleus Accumbens - increased NA, DA at the synaptic cleft 2) also a local anaesthetic - ionised cocaine blocks sodium channels to block sodium influx

Question 40

what effect does cocaine achieve by blocking the monoamine transporter?

Answer 40

increases dopamine concentration (and noradrenaline) at the nucleus accumbens this stimulate euphoria

Question 41

what other major effect apart from euphoria does cocaine have? how?

Answer 41

local anaesthetic blocks sodium channels

Question 42

how is cocaine HCl taken?

Answer 42

intranasally

Question 43

how is crack/freebase taken?

Answer 43

smoking

Question 44

why is GI administration of cocaine slow to have effects?

Answer 44

slow absorption due to ionisation in the stomach

Question 45

why is cocaine addictive?

Answer 45

has a rapid onset | the quicker the onset the more addictive

Question 46

how is cocaine metabolised?

Answer 46

by plasma cholinesterase's in the liver cocaine--> ecgonine methyl ester and benzoylecgonine

Question 47

what are the products of cocaine metabolism?

Answer 47

ecgonine methyl ester | benzoylecgonine

Question 48

how is cocaine excreted?

Answer 48

75-90% urine

Question 49

what are the low dose side effects of cocaine?

Answer 49

many due to increased noradrenaline (not all due to NA though): - increased motor activity - risk of epilepsy - tachycardia - vasoconstriction - hypertension - atherosclerosis progression - increased platelet activation contribution to CVD

Question 50

which of the low dose side effects of cocaine are due to increased noradrenaline levels?

Answer 50

- tachycardia - vasoconstriction - hypertension

Question 51

why may low dose cocaine increased MI risk?

Answer 51

side effects like: - tachycardia - vasoconstriction - hypertension along with: - atherosclerosis progression - platelet activation contribute to the MI risk NB these are all low dose cocaine side effects

Question 52

what are the HIGH dose side effects of cocaine?

Answer 52

- CNS depression - respiratory failure - convulsions - death