Drugs of abuse 2

Question 1

Where does cocaine come from

Answer 1

Erthryoxylum coca leaves….

Question 2

Outline the types of cocaine and how they are taken

Answer 2

1. ‘Paste’ …. extract around 80% of the cocaine from leaves using an organic solvent
2. ‘Cocaine HCl’ - extract the cocain from the above paste, and then put it in acid. This form can then be dissolved in water and is useful for anaesthetic.

Both I.v. Oral, intranasal. They can’t be smoked or heated as they have a high boiling point, and will be destroyed before they reach this.

The solution to this is:

3. ‘Crack’ - precipitate the cocain HCl with an alkaline solution (e.g. baking soda). You end up with cocaine rocks (i.e. the salt of the acid and base)

Then you can dissolve the crack in a non-polar solvent such as ammonia or ether= ‘Freebase’

For inhalation

Question 3

What are the problems with cocaine on the nasal septum

Answer 3

Because it causes vasoconstriction and the tissue becomes necrotic

Question 4

Outline issues with boiling point and solubility

Answer 4

Cocain HCl has a high boiling point, and would break down before being heated high enough to smoke… so bad if you want to abuse the drug….. so people would snort instead of inject or oral

But with crack cocaine or freebase, then the boiling point is lower so the drug can be inhaled before being destroyed by heat

Cocain HCl is more water soluble, crack cocaine is more lipid soluble (easily diffuses across lipid membrane)

Freebase allows you to make crack cocaine more pure (doesn’t have the baking soda… but more dangerous to handle)

Question 5

Outline the effect of the rate of absorption on the length of action

Answer 5

Snort/ oral leads is slow absorption but longer action

Inhalation and IV fast absorption and reduced duration of action

Question 6

Where is cocaine absorbed if taken orally

Answer 6

The pKa is 8.7, which is greater than the stomach.

High ionisation in the stomach…. so not absorbed until the intestine

Slower absorption than if it was unionised in the stomach, in which case it is absorbed in the stomach

Question 7

Outline them metabolism of cocaine

Answer 7

75%-90% metabolised to inactive metabolite (ecgonine methyl ester and benzoylecgonine)

T1/2 is 20-90mins

Broken down by both plasma AND liver cholinesterases

YOU CAN REMEMBER THIS BECAUSE COCAINE IS A LA! AND IT’S THE ESTER FORM (ESTER SMOKES COCAINE) SO IT HAS TO BE AN ESTERASE BREAKING IT DOWN!

Question 8

How do pharmacokinetics of cocain affect addictive ness

Answer 8

Speed of onset of euphoria (as the association between the drug and euphoria is great)

And quick loss as well due to being rapidly broken down in the blood stream and the liver

Question 9

Explain the action of cocaine at high dose

Answer 9

The HCl form is a local anaesthetic

Na+ channel blocker but cannot block it from the blood side of the membrane… has to difffuse across the plasma membrane and then can access the open channels or diffuse into a closed channel from the inside

Question 10

Why must cocaine be uncharged for Na+ Channel blockade

Answer 10

So that the cocaine can pass through the plasma membrane and block Na+ channels from the inside

Question 11

What’s does cocain do at high and low dose

How does cocaine increase sympathetic activation

Answer 11

So cocaine acts as a sympathetic NS activator (see below).

However it is also a class 1 antiarrythmic agent (local anaeasthetic effect of blockng Na+ and K+)

These effects are opposing.

Enhanced sym. occurs as low cocaine dose, whereas local anaesthetic action occurs at higher dose

Increases synpathetic:

1. Reduces reuptake of NA
2. Centrally increases sympathetic outflow
3. Sensitises adrenergic nerve endings to NA

NOTE: NOT JUST NA, ALSO AFFECTS REUPTAKE OF DA AND 5-HT!

Question 12

Explain the euphoric effect of cocaine

Answer 12

At the nucleus accumbens, cocaine blocks the dopamine reuptake and this increases concentration of dopamine in the synapse

Increased D1R at the NAcc

Question 13

Low dose cocaine does what

Answer 13

Inhibits reuptake of serotonin and NA as well as dopamine

Question 14

Effect of normal cocaine effect and also effect in tolerance (chronic users)

Explain why tolerance occurs

Answer 14

Initial doses is positive/reinforcing (mood amplification, heightened energy, sleep disturbance, increased libido, anger verbal agression)

Further doses are negative/stereotypic (irritability, anxiety, exhaustion, disjointed flight of ideas, total anrexia)

BECAUSE cocaine increases concentration of dopamine in the synapse but by blocking reuptake, the neurone fails to replenish the dopamine. Further cocaine use results in much lower euphoria

Question 15

Harmful effects of cocaine on the heart

Answer 15

1. Increased MO demand:

Increased NA/ central sympathetic output increases:

1. HR
2. contractility,
3. blood pressure,
4. Reduces MO supply

Increased NA/ central sympathetic output leads to:

1. coronary vasoconstriction,
2. platelet activation (which can lead to atherosclerosis
3. Endothelial injury (due to increased HR, contractility and BP), which can lead to atherosclerosis and reduced MO.

Points 1 and 2 all lead to myocardial ischaemia and infarction.

3. Arrhythmias

This can be due to the myocardial ischaemia, but also

At the higher doses of cocaine use, the local anaesthetic action (i.e. Na+ blocking action) kicks in. This can lead to reduced left ventricular function.

Inflammation (also due to local anaesthetic effect) can lead to endothelial injury and reduced left ventricular function.

The arrythmia can lead to sudden death.

Question 16

What’s is the effect of cocaine of hyperthermia

Answer 16

1. Cocaine increases heat production:

SNS activation
increase muscle activity (voluntary and involuntary, and due to agitation)

2. Cocain affects heat dissipation

Cocaine reduces vasodilation (bad for heat dissipation) but increases sweat production (good for heat dissipation)

But there is change in the set point for sweating and vasodilation (3 fold higher before sweating and dilation occurs)

Particularly naive users

Question 17

WHAT time tissue half life of cocaine and what is the onset

Answer 17

90 minutes (compared to 7 DAYS for cannabis!)

Onset is seconds

Question 18

WHy isn’t there a risk of death like with heroin Andy alcohol

Answer 18

Because it is a stimulant so cant shut down the cardiorespiraotry centre in the medulla

Question 19

Outline the compoennets of cigarette smoke

Answer 19

Volatile (95%):
Nitrogen, CO, CO2, Benzene, HCN

and

particulate (5%):
Alkaloids (NICOTINE)
Tar

Question 20

How comes smoking cigarette has lowest nitoctine absorption compared to the other administratin routes, despite having excellent perfusion

Answer 20

Only about half of the smoke actually gets to the lungs, and only half of that gets deep enough into the lungs for absorption

Question 21

What is the lipid solubility of nicotine

Answer 21

Quite good

Question 22

WHere is the nicotine found in cigarette smoke

Answer 22

Within the particulates (not volatile)… nictonine found in the tar droplets in the lungs, and absorbed through this

Question 23

Outline how nicotine can be administered

Answer 23

Nicotine spray – 1mg

Nicotine Gum – 2-4mg Nicotine

Cigarettes – 9-17mg nicotine

Nicotine Patch – 15-22mg/day

Question 24

Outline the bioavailability of nictonine via the different routes

Answer 24

PATCH is highest, CIGARETTE SMOKE is lowest (why!?)

Nicotine spray – 1mg 20-50%

Nicotine Gum – 2-4mg Nicotine 50-70%

Cigarettes – 9-17mg nicotine 20%

Nicotine Patch – 15-22mg/day 70%

Question 25

Why can nicotine be chewed in gum and be absorbed in the buccal cavity but not absorbed in the buccal cavity in smoke

Answer 25

IN SMOKE NITOCTINE IS IONISED ionised so high pKa of 7.9 (cigarette smoke ACIDIC) and no buccal absorption but not ionised in gum so absorbed in mouth

EVEN THOUGH NICOTINE IONISED IN SMOKE, CAN STILL BE ABSORBED DOWN IN THE LUNGS BECAUSE THE AVEOLI DON’T PROVIDE MUCH BARRIER, ANYTHING GETS ACROSS REALLY EVEN IF IONISED

‘absorption in the alveoli is independent of pH’

Question 26

Outline differences in administration with respect to weening

Answer 26

With cigarette smoking there is a huge difference between the peak effect just after smoking and plasma concentration 30 minutes later (which is why smokers continuously smoke to top back up to peak level)

With the other methods eg gum and skin etc, the dose is lower but it is smoother such that the peak dose does not fall dramatically

(note that the dose of cigarette smoke is higher, despite its poor bioavailability, due to being acidic, because the dose in cigarette smoke is higher than the dose being given in attempts to ween off nicotine)

Question 27

How is nicotine metabolised

What is the half life of nicotine

Answer 27

Quickly converted to inactive metabolites (by CYP2A6) called called conitine

t1/2 = 1-4hrs

70-80%

Note that the half life is slightly longer than the cocain half life and that is because the cocaine is also broken down in the blood whereas the nicotine is only broken down in the liver

Question 28

How does nicotine work

Answer 28

It binds to NAChR ion channel linked so influences both SNS and PNS… activating autonomic nervous sytem

Question 29

How does nicotine induce euphoria

Answer 29

Nicotine activates NAChR on the dopaminerigic neuron in the VTA, so increases dopamine on the D1R

Question 30

How does nicotine produce poor CVS effects, and compare with cocain

Answer 30

No local anaesthetic effect….
Less likely To produce acute cardiovascular effects than with cocaine (because no Na+ channel blocking/pro-inflammatory respinse)

Basically same as cocaine in terms of increasing sympathetic output which incrases platelet activation, coronary vasoconstriction, and Increasing HR, BP and contractility

BUT nicotine also worsens the lipd profile, so as well as the platelet activtion/endothelial injury causing atherosclerosis, there is also increased FFAs, increased VLDL and LDL

Question 31

What is the effect of nicotine on metabolic rate

Answer 31

Increased metabolic rate (catabolic effect…. due to SNS)

Reduces appetite and weight gain occurs after giving up

Question 32

Outline the effect of nicotine on neurodegenerative disorders

Answer 32

Protective

In Parkinson’s increases brain CYPs that can break downs neurotoxins which cause the disease

Alzheimer’s Disease: reduce beta-amyloid toxicity

and amyloid precursor protein (APP)

Question 33

How does caffeine act as a stimulant

Answer 33

It is an adenosine receptor antagonist…. adenosine binds to adenosine receptor on the dopaminergic neurons and decreases dopamine release AND

also decreases D1 receptor activation on the NAcc neuron

Caffeine is an antagonist for adenosine so it blocks both these effects

Question 34

Does vaping remove all the effects of smoking

Answer 34

Removes pulmonary effects associated with the volatile matter,

but the nicotine in the particulate matter is still causing all of those CVS effects

Question 35

How are nicotine and cocaine similar in pharmacookinetics

Answer 35

Because they are raidly absorbed (inhalation) but then rapidly metabolised, both have short half life (cocain shorter than nicotine)

Question 36

Why is the caffeine less euphoria causing

Answer 36

Caffeine is generally orally administered – so the euphoria effect is less obvious

Question 37

How do you get the most cocaine into the bloodstream

Answer 37

IV…. even though inhalation is faster, less is lost. Lots is lost with inhalation so there is lower bioavailability

Question 38

Outline the effects of cocaine on the heart at high and low dose

Answer 38

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 39

Why can coaine overuse results in seizure

Answer 39

due to a vasoconstricting effect in the brain (reduced blood flow to certain parts of the brain). Cocaine stimulates hyperpyrexia. The combination of vasoconstriction and hyperpyrexia are associated with seizure induction and epilepsy.