PHAR 4: Applying PD/PK Theory - Stimulants

Question 1

What are stimulants?

Answer 1

• drugs that typically stimulate or increase the activity of nerves within the central nervous system

Question 2

Observe the learning outcomes of this session

Answer 2

Question 3

Give two examples of stimulants

Answer 3

• cocaine
• nicotine

Question 4

Where do cocaine and nicotine come from?

Answer 4

• they are both plant based compounds:
• cocaine: erythroxylum coca plant
• nicotine: nicotiana tabacum

Question 5

What is the main reason cocaine and nicotine are used?

What does the route of administration have to the with its effect?

Answer 5

• The main reason individuals ‘abuse’ these drugs is to induce a euphoric ‘high’ in the brain.
• The speed of onset for this euphoric ‘high’ has a huge impact on the reinforcing effect of these drugs.
• The faster the ‘high’ is produced, the more powerfully reinforcing the effect of the drug.
• Different routes of administration are associated with different speeds of onset.

Question 6

What are the common routes of administration for cocaine and nicotine and their speeds of onset for peak effect in the brain?

Answer 6

• intra-venous: 3 min
• intra-nasal: 15 min
• inhalational: 1.5 min
• oral: 60 min

Question 7

When administered via the intra-nasal route, what is the precise route via which the drug accesses the brain?

Answer 7

• There is no direct route from the nasal passage to the brain.
• The drug will enter the nasal sinus. From here, it will need to cross the mucous membranes of the nasal sinus and enter the venous system.
• The venous system will then return the drug to the heart and from here it will finally be able to enter the relevant arteries that can access the brain.

Question 8

Why does inhalation produce a more rapid effect than intra-venous administration?

Answer 8

• for intra-venous administration:
• when injecting, the drug will go straight into the venous system, with the blood returning to the right atrium, right ventricle
• then ejected into the pulmonary circulation, returned to the left side of the heart and ejected into systemic circulation
• from there, it can access the brain
• inhalational:
• any drug that gets down to the alveoli diffuses across incredibly fast
• so there is a very rapid transit from lungs into the pulmonary venous system
• from there, it goes straight to the left side of the heart
• this method does not require the right side of the heart

Question 9

Why was crack cocaine created?

Answer 9

• It is perhaps no surprise that cocaine/nicotine users tend to prefer the inhalational method for drug administration, since the effects are produced more rapidly via this route.
• In fact, the invention of ‘crack’ cocaine was primarily driven by a desire to produce a version of cocaine that could be inhaled.
• Cocaine hydrochloride is the medicinal form of cocaine that is also associated with ‘snorting’.
• However, cocaine hydrochloride degrades when heated.
• If you take cocaine hydrochloride solution and mix with an alkaline solution, the precipitate formed is ‘crack’ cocaine and can be heated and subsequently inhaled.

Question 10

Describe the metabolism of cocaine

• include its half life

Answer 10

• metabolised in the liver
• by cholinesterase enzymes
• can also be metabolised by plasma cholinesterases
• there are no active metabolites, so metabolism effectively deactivates the drug
• the half life for cocaine is 20-90 min

Question 11

Describe the metabolism of nicotine

Answer 11

• metabolised in the liver
• by cytochrome P450 enzymes to cotinin
• there are no active metabolites, so metabolism effectively deactivates the drug
• the half life for nicotine is 1-3h

Question 12

What aspects cause cocaine and nicotine to be so addictive?

Answer 12

• the faster the onset of action, the more powerfully addicting the drug effect tends to be:
• With the inhalational route, cocaine/nicotine-induced euphoria should occur within seconds with peak effects occurring within a couple of minutes.
• Thus the drug user develops a strong association (reinforcing effect) between inhaling the drug and inducing euphoria.
• metabolism: the faster the drug is metabolized the quicker the drug effect is lost.
• This drives further drug use to restore the drug effect.
• Therefore, the rapid metabolism of cocaine and nicotine also contributes to the addictive potential of these drugs.
• Cigarette smokers regularly smoke many cigarettes a day; Cocaine users often ‘binge’ on cocaine (take the drug repeatedly over a short period of time).
• The rapid metabolism of these drugs means that in order to maintain plasma levels of cocaine and nicotine within the range where effects are observed, you need to constantly re-administer the drug.

Question 13

What is regarded as the most powerfully addictive drug on the planet?

Answer 13

• ‘Crack’ cocaine is regarded as the most powerfully addictive drug on the planet.
• You can inhale the drug leading to rapid effects and those effects are very quickly lost due to efficient metabolism leading to the desire to take more cocaine (drug seeking behavior).

Question 14

Describe the drug selectivity of nicotine and cocaine

Answer 14

• nicotine is relatively selective for one target
• cocaine is less selective and can bind to multiple targets.
• The main targets for cocaine are catecholamine reuptake proteins and sodium channels.
• You should also remember from session 1 that selectivity is linked to dose.
• In the case of cocaine, it is more likely to bind to the catecholamine reuptake proteins at low dose, whereas its ability to interact with sodium channels is more likely to occur at higher doses.

Question 15

What is the effect of cocaine on catecholamine reuptake?

Answer 15

• cocaine possesses an inhibitory effect on catecholamine reuptake
• The actual cellular mechanism for catecholamine reuptake is not completely understood

Question 16

Observe the chemical structure of cocaine and two catecholamines, noradrenaline and dopamine

Describe their similarities

Answer 16

• There are some similarities within these structures.
• They all possess a lipophilic ring structure, an intermediate linking bond, and an amine group.
• it was mentioned before that cocaine acts as a reuptake inhibitor, but in reality, cocaine (and other reuptake inhibitors) are substrates for the reuptake protein just like noradrenaline and dopamine.
• The difference is that reuptake of cocaine is much slower than noradrenaline and dopamine.
• Again, if we consider the structure of the three chemicals, there is some logic to this.
• The similarities in structure explain why these three chemicals might all act as substrates for catecholamine reuptake proteins.
• The differences might explain the speed of the reuptake process i.e. cocaine has a more complex tertiary amine group.

Question 17

Describe how dopamine is produced in dopaminergic nerve terminals

Answer 17

• tyrosine is a precursor to dopamine, which is produced via enzymatic conversion
• by tyrosine hydroxylase, which is a rate-limiting enzyme that converts tyrosine to DOPA
• then dopa carboxylase converts DOPA to dopamine
• dopamine vesicles now sit near the cell surface awaiting an action potential
• when the nerve is stimulated, an action potential will fire down the nerve to the nerve terminal
• this promotes calcium influx, which is particularly important in mediating exocytosis
• the action potential stimulates dopamine exocytosis, and now dopamine is free in the synapse
• thousands of molecules of dopamine can now bind to dopamine receptors
• when it does, dopamine receptor complex is formed and this transduces a response

Question 18

Describe how dopamine is removed in dopaminergic nerve terminals

Answer 18

• dopamine must be removed from the synapse, otherwise, the postsynaptic cell is going to be permanently stimulated
• the reuptake protein on the presynaptic terminal will come across dopamine molecules as they bounce around the synapse
• dopamine molecules will be equally likely to come into contact with the reuptake protein and the dopamine receptor
• if that happens the reuptake protein basically takes the dopamine, removes it from the synapse and flips it across the membrane back into the presynaptic terminal.
• over time, all of the dopamine molecules eventually are going to come into contact with those reuptake proteins and be removed from the synapse.
• At that point, the effect is pretty much lost the dopamine is all now back within the presynaptic terminal and then what tends to happen next is that dopamine is then metabolized, so its broken down and actually the nerve terminal can reuse some of those metabolites if necessary to recreate dopamine and the whole process continues in that way.

Question 19

What would the presence of cocaine do to the pharmacodynamic profile of dopamine?

Answer 19

• the number of dopamine-receptor interactions increase
• affinity of dopamine for the dopamine receptor has no change

Question 20

What does the presence of cocaine do to dopamine action?

Answer 20

• cocaine ‘blocks’ the dopamine reuptake protein
• cocaine, like dopamine, is taken by this transport protein and flipped from the synapse back into the presynaptic terminal, but in the case of cocaine, it is a very slow process
• therefore, if cocaine is being utilized by that particular transport protein at that moment in time, dopamine cannot access that reuptake protein and therefore cannot be removed from the synapse.
• dopamine will have been released into the synapse.
• It can there access the receptor if it can access the receptor it can produce a response.
• Normally it would also then slowly be removed from the synapse by the reuptake protein, but that process is being significantly slowed by the presence of cocaine.
• As a result, dopamine molecules remain in the synapse for a much greater length of time and during that time they are free to access the dopamine receptor.
• So what is going to happen in this situation is you’re going to get a lot more dopamine receptor complexes being formed and therefore you’re going to get a much larger dopamine response.

Question 21

Does cocaine affect the affinity of dopamine for the receptor?

Answer 21

• No, it doesn’t.
• Each individual molecule of dopamine still has the same affinity for the receptor.
• It’s not that affinity or efficacy are changing, it is simply the case that far more of these receptor complexes are being formed and therefore the cumulative effect is a much more powerful effect through the postsynaptic cell or postsynaptic neuron.

Question 22

How does cocaine bind to sodium channels?

Answer 22

• sodium channels are embedded in the lipid membrane.
• The binding site for cocaine is actually on the intracellular side of the membrane
• i.e. cocaine will need to be able to cross the plasma membrane in order to access the binding site.
• if you consider the structure of cocaine, it certainly appears to possess traits that would make the drug fairly lipid soluble
• e.g. a benzene ring, an uncharged amine side group

Question 23

Represent cocaine in an ionic equation

Link this with the Henderson-Hasselbalch equation

Answer 23

• Cocaine is a weak base

Question 24

Calculate the ratio of ionised to unionised cocaine ratios

Answer 24

Question 25

What form does cocaine need to be to cross the lipid membrane?

What form is most effective when binding?

Answer 25

• cocaine needs to be in an unionised form to cross the lipid membrane and access the sodium channel binding site located on the intracellular side of the membrane.
• What is interesting is that it is the ionised form of the compound that can bind to the binding site most effectively
• (this is actually a general rule i.e. unionised forms cross lipid membranes most effectively but ionised forms possess the polar side chains most likely to interact and bind to protein targets).

Question 26

Why is cocaine an effective local anaesthetic agent

• hint: pH partition hypothesis

Answer 26

• The pH partition hypothesis dictates that there are more ionised molecules (i.e. BH+) of cocaine in the extracellular fluid than unionised molecules (i.e. B).
• However, there are still sufficient unioinised cocaine molecules to allow appreciable diffusion across the plasma membrane.
• Remember from session 2, we were often dealing with ratios of 10,000 to 1.
• In comparison, ratios of approximately 10 to 1 do not result in anywhere near the same degree of ion trapping.
• Once across the plasma membrane, the drop in pH leads to a larger degree of ionisation of cocaine, which is important since the ionised form is able to access the sodium channel binding site.
• The end result of this interaction is a blockade of the sodium channel.
• The ability of cocaine to block sodium channels is the reason why cocaine (and related drugs) are effective local anaesthetic agents.

Question 27

What is the target for nicotine?

What is its endogenous agonist?

Answer 27

• The target for nicotine is the nicotinic acetylcholine receptor.
• The endogenous agonist for this receptor is obviously acetylcholine, but this receptor was named due to the fact that nicotine was the first agonist that was identified that bound to this receptor.

Question 28

What is the nicotinic acetylcholine receptor’s function?

Answer 28

• it is a key component of the autonomic nervous system.
• The autonomic nervous system is one arm of the peripheral nervous system and regulates a huge number of vital body functions such as:
• heart rate
• gastrointestinal function
• sweating
• pupil dilation
• blood glucose levels …and many more

Question 29

Where else are nicotinic receptors present?

Answer 29

• within the somatic nervous system – this is another branch of the peripheral nervous system, in this case the conscious control of skeletal muscle.

Question 30

Describe the structure of the nicotinic acetylcholine receptor

Answer 30

• This is an ion channel linked receptor.
• The receptor consists of five subunits that surround the central ion channel pore.
• Acetylcholine binds to the relevant subunit and promotes ion channel opening and the movement of ions (predominantly sodium and calcium) from the extracellular side to the intracellular side of the membrane.

Question 31

Describe the location and the roles of the two major nicotinic acetylcholine receptors

Answer 31

• autonomic nervous system:
• the autonomic nervous system has a two neurones set up and those two neurones are termed the preganglionic and the postganglionic neurones.
• The preganglionic neurone will originate either in the brain or somewhere within the spinal cord.
• The preganglionic nerve then synapses with the postganglionic nerve in something that’s called a ganglion.
• the nicotinic acetylcholine receptor is the receptor that propagates that action.
• You can see from the diagram that the preganglionic neuron is releasing acetylcholine, acetylcholine is the agonist for the nicotinic acetylcholine receptor.
• So within the ganglion, you’ve got acetylcholine release, it’s activating the nicotinic acetylcholine receptor which is then activating the postganglionic neuron.
• That postganglionic neurone then heads off to a peripheral organ
• the role of the nicotinic acetylcholine receptor in the autonomic nervous system is to propagate the signal from preganglionic to postganglionic neurone
• somatic nervous system:
• In this case, you don’t have the same two neurones set up, you just have one long motor neurone and again that’s going to originate from spinal cord or brain and that motor neurone projects all the way down onto the skeletal muscle.
• A nicotinic acetylcholine receptor, in this case, will be found on the skeletal muscle itself.
• So the acetylcholine is released from the motor neurone, that activates the nicotinic acetylcholine receptor and activating the nicotine acetylcholine reset on the skeletal muscle is what then prompts contraction of the skeletal muscle.

Question 32

Observe the diagram of the reward pathway and the targets for cocaine and nicotine

Answer 32

• the euphoric ‘high’ is produced via stimulation of dopaminergic neurons within the reward pathway.
• These neurons originate in the ventral tegmental area and project to the nucleus accumbens (see diagram below).
• Activation of these neurons leads to dopamine release in the nucleus accumbens and feelings of reward/euphoria.

Question 33

Describe the reward pathway for nicotine

Answer 33

• stimulation of these neurons leads to feelings of euphoria.
• This would involve depolarisation of the neurone at the cell body in the ventral tegmental area.
• An action potential would pass along the axon and promote dopamine release within the nucleus accumbens.
• Dopamine would activate the dopamine (D1) receptors which would lead to feelings of euphoria.
• Dopamine would then be removed from the synapse via the dopamine transporter and the euphoric effect would be lost.
• For Nicotine:
• activation of the nicotinic receptor promotes/increases neuronal depolarisation via sodium influx.
• As with an endogenous signal, nicotine-induced depolarisation of this dopaminergic neurone leads to increased dopamine release into the synapse, and the subsequent increased activation of the dopamine (D1) receptor increases feelings of euphoria.

Question 34

Describe the reward pathway for cocaine

Answer 34

• stimulation of these neurons leads to feelings of euphoria.
• This would involve depolarisation of the neurone at the cell body in the ventral tegmental area.
• An action potential would pass along the axon and promote dopamine release within the nucleus accumbens.
• Dopamine would activate the dopamine (D1) receptors which would lead to feelings of euphoria.
• Dopamine would then be removed from the synapse via the dopamine transporter and the euphoric effect would be lost.
• For Cocaine:
• there is no effect on neuronal depolarisation.
• Cocaine blocks/slows the dopamine reuptake transporter.
• As a result dopamine is removed more slowly from the synapse.
• The longer that dopamine remains in the synapse the greater the number of dopamine-receptor interactions will be produced increasing feelings of euphoria.

Question 35

What are the shared peripheral stimulant effects shared by cocaine and nicotine?

Answer 35

• Cocaine and nicotine also possess certain shared peripheral stimulant effects.
• This is predominantly due to the ability of both drugs to stimulate/mimic the sympathetic nervous system.
• The sympathetic nervous system is one branch of the autonomic nervous system described previously (the other branch is the parasympathetic nervous system).
• The sympathetic nervous system (as with the autonomic nervous system as a whole) can be stimulated by nicotine via the nicotinic acetylcholine receptor (see diagram below).

Question 36

How does the stimulant effect by cocaine and nicotine on the sympathetic nervous system manifest itelf?

Answer 36

• One area that is clearly affected is cardiovascular function.
• Both cocaine and nicotine significantly influence the cardiovascular system via a stimulated sympathetic nervous system.
• This leads to increased heart rate as well as increased vasoconstriction within blood vessels – the combined effect is to increase blood pressure.
• As you will see in the section on toxicity, the most dangerous adverse effects of both cocaine and nicotine are related to their actions on the cardiovascular system.

Question 37

What are the shared effects of cocaine and nicotine?

How do they contribute to cardiovascular toxicity?

Answer 37

• increased heart rate and increased contractility
• leads to increased blood pressure
• this causes an increase in the oxygen demand of the heart (increased myocardial oxygen demand)
• which can lead to endothelial injury
• coronary vasoconstriction:
• this leads to a decreased blood flow to the heart
• increased blood pressure and oxygen demand above and the opposite here can lead to a problem too
• increased platelet activation
• contributes to atherosclerosis
• less blood gets through to the heart
• leading to a mismatch between the amount of oxygen the heart requires and the amount it is actually being supplied
• leading to myocardial schema
• can lead to infarction, damage to the heart wall
• which can lead to arrhythmias and sudden death

Question 38

Which is the more powerful agent in terms of cardiovascular toxicity?

Answer 38

• cocaine is probably the more powerful agent and therefore the more dangerous agent.
• You can use heart rate as a biomarker for potency and effectively cocaine can probably induce about a 50% increase in your heart rate, nicotine very rarely gets your heart rate to increase by more than about 20%.
• That gives you some indication that cocaine is probably the more powerful drug in this case.

Question 39

What are some cardiovascular effects specific to nicotine?

Answer 39

• We know that nicotine alters the blood lipid profile and you can see that in red in this diagram.
• So you’re going to get more free fatty acids and that’s going to increase the sort of bad fats, the very low-density and low-density lipoproteins and the increased presence of these lipoproteins in the blood carry a large atherogenic risk.
• So, they are going to contribute to the development of atherosclerosis this will increase the long-term risk of cardiovascular disease
• This is less of a problem in terms of acute toxicity as this is more of a chronic thing.
• The atherosclerotic problem is a chronic problem.

Question 40

What are some cardiovascular effects specific to cocaine?

Answer 40

• if you consider the additional cardiovascular effects of cocaine, they can definitely contribute to acute toxicity.
• We’ve already talked about the fact that cocaine can block sodium channels - that’s what gives them their local gives it its local anesthetic effect.
• However, if you block sodium channels in the heart that’s obviously going to potentially lead to dysregulations in cardiac rhythm and when you then also add in the fact that cocaine is known to induce inflammation and that can be an acute event that inflammation is known to both contribute to a problem with left ventricular function.
• It can also exacerbate the endothelial injury that we’ve previously discussed.
• So cocaine, because it impairs sodium transport, because it causes an acute inflammation, those two factors together can lead to a much greater acute dysfunction with regard to the heart and therefore it’s far more likely for cocaine to cause acute cardiac problems.