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LCRS Pharma > Drugs of Abuse: Cocaine and Nicotine > Flashcards

Drugs of Abuse: Cocaine and Nicotine Flashcards

1
Q

what is the plant for cocaine?

A

Erythroxylum coca

0.6-1.8% cocaine

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2
Q

what are the forms of cocaine?

A

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).

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3
Q

which forms of cocaine are purer and therefore stronger?

A

crack and freebase

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4
Q

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

A

IV and inhalation have fast onset (short-lasting)

smoking, nasal and oral have slow onset

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5
Q

why does oral intake of cocaine have a slower onset?

A

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

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6
Q

what are the two metabolites created by cocaine metabolism?

A 
75-90% of cocaine is rapidly metabolised into:
	Ecogonine methyl ester.
	Benzoylecgonine.
these are inactive metabolites
by plasma cholinesterases
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7
Q

what is the half life of cocaine?

A

20-90 minutes

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8
Q

what carry out the metabolism of cocaine?

A

plasma (in the blood) and liver cholinesterases

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9
Q

why does the metabolism of cocaine make it addictive?

A

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

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10
Q

what are the 2 major effects of cocaine?

A
  • euphoria (re-uptake inhibition )

- local anaesthetic (sodium blockage)

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11
Q

how does cocaine act as a local anaesthetic?

A

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

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12
Q

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

A

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

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13
Q

how does cocaine cause euphoria?

A

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

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14
Q

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

A

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.

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15
Q

how does cocaine use lead to an MI?

A
  • 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

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16
Q

how does cocaine promote thrombosis?

A

Cocaine promotes thrombosis by activating platelets, increasing platelet aggregation

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17
Q

how does cocaine cause vasoconstriction?

A

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

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18
Q

how does cocaine cause hyperthermia?

A

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]

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19
Q

what is a CNS effect of cocaine?

A

vasoconstriction causes hyper-pyrexia and then epilepsy

at high dose cocaine causes CNS depression

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20
Q

what is the plant for nicotine?

A

nicotana tabacum

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21
Q

what are the two major product of cigarettes?

A

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

22
Q

what are the different types of nicotine dosage?

A

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.

23
Q

why is there no buccal absorption of nicotine from cigarettes?

A

pKa of 7.9, cigarette smoke is acidic

absorption in the alveoli however is independent of pH

24
Q

what leads to nicotine addiction?

A

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

i.e. rapid onset but short duration of action

25
Q

what is the half life of nicotine?

A

1-4 hours

26
Q

how is nicotine metabolised?

A

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

27
Q

where does nicotine bind and what effect does this have?

A

binds to nicotinic receptors and stimulates Na+ transport

28
Q

what are the molecular effects in the CVS by nicotine?

A

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.
29
Q

what effect does nicotine have on fats and cholesterol?

A

Increased lipolysis, FFAs, VLDLs, decreased HDL

increased free fatty acids contributes to atherosclerosis but its a slower build up compared to cocaine

30
Q

what effect does nicotine have on vasodilators and vasoconstrictors?

A
  • Increased TXA2 (–> platelet activity)

- reduced NO.

31
Q

how does nicotine cause euphoria?

A

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

32
Q

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

A

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
33
Q

how does nicotine have protective effects against neurodegenerative disorders?

A

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)

34
Q

what is the effect of caffeine in the reward pathway?

A

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)

35
Q

metabolism of nicotine

A

CYP2A6 in the liver

nicotine–> cotinine

36
Q

how is nicotine excreted?

A

urine and saliva

37
Q

what are the effects of nicotine?

what risk due these effects combined increase?

A
  • 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

38
Q

why is nicotine addictive?

A

rapid onset of effects but short lasting (distribution)

39
Q

what is cocaine?

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

A

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

40
Q

what effect does cocaine achieve by blocking the monoamine transporter?

A

increases dopamine concentration (and noradrenaline) at the nucleus accumbens

this stimulate euphoria

41
Q

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

A

local anaesthetic

blocks sodium channels

42
Q

how is cocaine HCl taken?

A

intranasally

43
Q

how is crack/freebase taken?

A

smoking

44
Q

why is GI administration of cocaine slow to have effects?

A

slow absorption due to ionisation in the stomach

45
Q

why is cocaine addictive?

A

has a rapid onset

the quicker the onset the more addictive

46
Q

how is cocaine metabolised?

A

by plasma cholinesterase’s in the liver

cocaine–> ecgonine methyl ester and benzoylecgonine

47
Q

what are the products of cocaine metabolism?

A

ecgonine methyl ester

benzoylecgonine

48
Q

how is cocaine excreted?

A

75-90% urine

49
Q

what are the low dose side effects of cocaine?

A

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

50
Q

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

A
  • tachycardia
  • vasoconstriction
  • hypertension
51
Q

why may low dose cocaine increased MI risk?

A

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

52
Q

what are the HIGH dose side effects of cocaine?

A
  • CNS depression
  • respiratory failure
  • convulsions
  • death

LCRS Pharma (32 decks)

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