Drugs of abuse 2

Question 1

Which plant does cocaine come from

Answer 1

Erythroxylum coca – leaves contain 0.6-1.8% cocaine.

Question 2

Describe the history of the uses of cocaine

Answer 2

Peruvian indians – Coca leaves + lime
(6th Century)

1886 – ‘Brain Elixir’ (Cocaine + Caffeine)

Question 3

Describe the different preparations of cocaine

Answer 3

§ Forms of cocaine – gets purer/stronger as you go down:

o Oral, IV, intranasal:

§ “Paste” – 80% cocaine (organic solvent).

§ “Cocaine HCl” – dissolved in acidic solution.

o Inhalational:

§ “Crack” – precipitated with alkaline solution (e.g. baking soda).

§ “Freebase” – dissolved in a non-polar solvent (e.g. ammonia + ether). - this gives you a purer version of cocaine

Question 4

What is important to remember about cocaine paste and cocaine HCL

Answer 4

Can’t be inhaled- the compound breaks down upon heating

Cocaine HCl can be used therapeutically as an anaesthetic.

Question 5

Explain the pKa-pH partition hypothesis

Answer 5

If a drug has a pKa greater than 7. It will be unionised in alkaline conditions (making it easier to access tissues), but ionised in acidic conditions (making it harder to access tissues).

Question 6

Explain why crack cocaine can be smoked

Answer 6

Cocaine use increased dramatically when the free-base form (‘crack’) became available as a street drug. When an aqueous solution of cocaine hydrochloride is heated with sodium bicarbonate, free-base cocaine, water, CO2 and NaCl are produced. The free-base cocaine is insoluble in water, precipitates out and can then be rolled into ‘rocks’ of crack. Free-base cocaine vaporises at around 90°C, much lower than the melting point of cocaine hydrochloride (190°C), which burns rather than vaporises. Thus crack can be smoked, with the uncharged free base being rapidly absorbed across the large surface area of the alveolae, giving rise to a greater CNS effect than that obtained by snorting cocaine.

Question 7

Which routes of administration of cocaine give the fastest absorption

Answer 7

Smoking (though IV gives a higher bioavailability)
Both as fast as each other
Both give a rapid and short-lasting high

Question 8

Why does smoking and oral absorption of cocaine have a lower bio availability than snorting it or injecting it

Answer 8

Cocaine itself has a PKa of 8.7
Smoke and the stomach are acidic
Therefore cocaine is ionised in smoke and in the G.I.T- meaning that it is poorly absorbed.
However, cocaine still readily diffuses across the alveoli.
Slower absorption, prolonged action

Question 9

Describe the metabolism of cocaine

Answer 9

Liver (75%-90%) – inactive metabolites: ecgonine methyl ester+ benzoylecgonine (metabolised by liver cholinesterases)
Plasma – it can be metabolised by plasma cholinesterases so it doesn’t last long in the plasma

Question 10

What is the half-life of cocaine

Answer 10

T1/2 - 20-90min

Question 11

How do you think that cocaine pharmacokinetics contribute to the addictive potential of the drug?

Answer 11

Very rapid onset (I.V and inhalational) - so strong association between stimulus and reward
Rapid clearance- euphoric effects lost quickly, so drug-seeking behaviour adopted to prolong euphoric effects.

Question 12

Describe how high dose cocaine can be used as a local anaesthetic

Answer 12

pH of blood is 7.4 pH of cell is 7.0 Therefore, as the pH of the blood is closer to the pKa of cocaine- it is more likely to be unionised in the blood, but ionised inside the cell. This means that cocaine can enter the cell through the lipid bilayer and block the Na+ channel in this HYDROPHOBIC pathway.
Alternatively, it can enter the cell and then become ionised, and then block the Na+ channel this way –HYDROPHILIC pathway

Channel closed in hydrophobic- but still open in hydrophoilic- but both prevent the influx of Na+ and thus the generation of an action potential- and thus prevent the transmission of painful stimuli.

Question 13

Describe the role of low dose cocaine in monamine re-uptake inhibition

Answer 13

o MAO-A re-uptake inhibitor (uptake 1).

o This can affect re-uptake of – NA/AD, DA, 5-HT.

o Note – this is not changing the affinity or efficacy dopamine, just increasing the DA in the synaptic cleft.

Cocaine binds to and inhibits the transporters NET, DAT and SERT (see Chs 15, 16 and 40), thereby producing a marked psychomotor stimulant effect, and enhancing the peripheral effects of sympathetic nerve activity.

Question 14

Describe how cocaine can cause euphoria

Answer 14

o Reduces re-uptake of DA into pre-synaptic neurone so more DA in the NAcc (from the VTA).

Thus more dopamine can act on D1 receptors to produce euphoric effects.

Question 15

What are the differences between the effects of cocaine in low dose/acute users and high dose/chronic users

Answer 15

Low dose – positive reinforcement – more energetic, need less sleep, more sociable, more talkative
High dose – negative/stereotypical effects – exhaustion, irritability, hostility, insomnia

Partly due to tolerance i.e. cocaine causes massive dopamine release but by blocking reuptake, the neurone fails to replenish the dopamine. Further cocaine use results in much lower euphoria, which can lead to other effects being manifest e.g. irritability.

Question 16

Outline how cocaine can lead to myocardial infarction

Answer 16

Cocaine is known to increase catecholamine activity (decreased monamine reuptake transporters) and also to act centrally to increase sympathetic output, and also increases the sensitivity of adrenergic nerve endings to norepinephrine.
As a result:
coronary vasoconstriction- which can also activate platelets as well as reducing myocardial oxygen supply
increased platelet activation- leading to atherosclerosis and thus a reduced myocardial oxygen supply- but also to endothelial injury and thrombosis
increased HR, contractility and BP- increasing myocardial oxygen demand (increased HR can also lead to endothelial injury)

Reduced Na+ transport- reduced left ventricular function – arrythmias, sudden death and endothelial injury

Inflammation- . In addition, 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.

Ultimately, the increased myocardial oxygen demand cannot be matched by the myocardial oxygen supply- leading to myocardial infarction, ischaemia and thus arrythmias and sudden death.

Question 17

What are the cardiovascular effects of reduced Na+ transport

Answer 17

Impaired LV function
Prolonged QRS and QT
Arrythmias.

Question 18

Describe the opposing cardiovascular effects of cocaine at different doses

Answer 18

Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine. Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters. Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions are more prominent at higher doses.

Question 19

How can cocaine prompt seizures

Answer 19

It causes vasoconstriction in various arteries of the brain and it also causes an increase in temperature (hyper-pyrexia), which can prompt seizures
It is linked to the development of epilepsy

Question 20

Describe how cocaine use is linked to hyperthermia

Answer 20

Cocaine overdose can lead to:
Agitation
Increased locomotor activity
Increased involuntary muscle contraction
All of these, by increasing the hydrolysis of ATP- will lead to increased heat production. In a hot environment this can lead to hyperthermia.
Normally, thus hyperthermia would be managed by increased heat dissipation- mediated by increased sweat production, cutaneous vasodilation and central threshold for thermoregulation.

However, althout cocaine enhances sweat production, it does inhibit cutaneous vasodilation (NA mediated) and elevates threshold for sweating/cutaneous vasodilation three fold

Question 21

What is sweating and cutaneous vasodilation mediated by

Answer 21

ACh

Question 22

Where does nicotine come from

Answer 22

Nicotana tabacum

Question 23

Describe the compositions of particulate and volatile matter in cigarette smoke

Answer 23

Cigarettes produce:

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

o 5% - particulates – e.g. alkaloids (nicotine), tar.

§ Nicotine diffuses out of the tar droplets in the lungs when deposited.
Volatile matter contains most of the carcinogenic elements (i.e benzene).

Question 24

Describe the different doses of nicotine in its various administration routes

Answer 24

Nicotine spray – 1mg (20-50%)

Nicotine Gum – 2-4mg Nicotine (50-70%) - not oral- instead liquid contains nicotine and diffuses across lipid membranes in the buccal cavity.

Cigarettes – 9-17mg nicotine (variable as most is exhaled and it depends on how you smoke it) (20%)

Nicotine Patch – 15-22mg/day (70%)

Question 25

Why is the bioavailability of cigarette smoke quite poor

Answer 25

Nicotine has a pKa of 7.9
Cigarette smoke is acidic- therefore nicotine is mostly ionised in cigarette smoke- meaning ther is no buccal absorption.
However, it will diffuse across the alveoli in the lungs to enter the bloodstream.

Absorption in alveoli independent of pH

Question 26

Which methods of administration of nicotine will lead to the fastest onset of peak activity

Answer 26

1. Cigarette
2. Spray
3. Gum/Inhaler/Tablet
4. patch

Question 27

Describe the metabolism of nicotine

Answer 27

o Nicotine T1/2 = 1-4 hours.

o Hepatic CYP-2A6 metabolises 70-80% à cotinine.

o Cotinine is not active and rapidly cleared in the urine.

Question 28

Explain why nicotine is so addictive

Answer 28

§ Administration:

o Again, short lasting action and a fast reduction in plasma concentration of nicotine leads to addiction.

The rapid decline results mainly from redistribution between the blood and other tissues; the slower decline is due to hepatic metabolism, mainly by oxidation to an inactive ketone metabolite, cotinine. This has a long plasma half-life, and measurement of urinary cotinine provides a useful indication of nicotine consumption.

Question 29

Describe the effects of nicotine on the CNS

Answer 29

At the neuronal level, nicotine acts on nicotinic acetylcholine receptors (nAChRs)
nAChRs are ligand-gated cation channels located both pre- and postsynaptically, causing, respectively, enhanced transmitter release and neuronal excitation
Increased Na+ influx.

Nicotine binds to nicotinic acetylcholine receptors on the cell bodies of dopaminergic neurones in the ventral tegmental area and stimulates sodium influx
This leads to an increase in the firing rate of the dopaminergic neurones, hence, more dopamine secretion
This will cause euphoria.

Question 30

Describe the effect of chronic nicotine use on the number of nAChRs

Answer 30

Chronic nicotine administration leads to a substantial increase in the number of nAChRs (an effect opposite to that produced by sustained administration of most receptor agonists), which may represent an adaptive response to prolonged receptor desensitisation. It is likely that the overall effect of nicotine reflects a balance between activation of nAChRs, causing neuronal excitation, and desensitisation, causing synaptic block.

Question 31

Describe the cardiovascular effects of nicotine

Answer 31

Takes longer to develop than cocaine- so cocaine stronger in this regard.
Like cocaine, nicotine increases sympathetic output and catecholamine release- leading to the cardiovascular effects already described.

Also, The plasma concentration of free fatty acids is increased, probably owing to sympathetic stimulation and adrenaline secretion. So we have increased FFA, LDL and VLDL which can lead to atheroscleoris and therefore myocardial infarction.

In addition it also promotes atherosclerosis and increases thromboxane A2 (hence increases platelet activity)

Question 32

Describe the metabolic effects of nicotine

Answer 32

Smokers weigh, on average, about 4 kg less than non-smokers, mainly because of reduced food intake and increased BMR; giving up smoking usually causes weight gain associated with increased food intake.

Question 33

Summarise the peripheral effects of nicotine

Answer 33

The peripheral effects of small doses of nicotine result from stimulation of autonomic ganglia (see Ch. 14) and of peripheral sensory receptors, mainly in the heart and lungs. Stimulation of these receptors produces tachycardia, increased cardiac output and arterial pressure, sweating, and a reduction of gastrointestinal motility. When people take nicotine for the first time, they usually experience nausea and sometimes vomit, probably because of stimulation of sensory receptors in the stomach. All these effects decline with repeated dosage, although the central effects remain. Secretion of adrenaline and noradrenaline from the adrenal medulla contributes to the cardiovascular effects, and release of antidiuretic hormone from the posterior pituitary causes a decrease in urine flow.6

Question 34

Describe the protective effects of nicotine against neuroodegenertive disorders

Answer 34

o Parkinson’s disease – increases brain CYPs (neurotoxin enzymes) à increased breakdown of neurotoxins.

o Alzheimer’s disease – decreases beta-amyloid toxicity AND decreases amyloid precursor protein (APP)

§ Nicotine seems to be PROTECTIVE against both diseases.

Question 35

Describe how caffeine may cause euphoria

Answer 35

Adenosine acts via adenosine receptors to decrease dopamine release and decrease D1 receptor function
Caffeine is an adenosine receptor antagonist so it will remove the inhibitory effect of adenosine
However, the inhibitory effect of adenosine is very minimal so caffeine will not cause a significant rise in dopamine release