PHAR 3: Applying PD/PK Theory to Depressants Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
What are depressants?
A
- drugs that typically suppress or slow the activity of nerves within the central nervous system
3
Q
Give some examples of depressants, narcotics/opioids and cannabinoids
Why are there crossovers?
A
- Classified as depressants – alcohol, benzodiazepines and barbiturates.
- Classified as narcotics/opioids – opioid-like drugs are clearly depressant drugs in general.
- Classified as cannabinoids – cannabis-like drugs are also depressant in general, but also have hallucinogenic properties.
4
Q
Observe the chemical structure of ethanol
A
5
Q
What does cannabis actually refer to in terms of its components?
Which is the most well studied?
A
- Cannabis actually refers to the active components of the cannabis sativa plant.
- This plant contains over 400 compounds and over 60 active cannabinoids (the active components of cannabis).
- In order to compare alcohol and cannabis, we need to choose just one of these cannabinoids.
- The most potent and well studied of these is Δ9-tetrahydrocannabinol (Δ9-THC).
6
Q
What is the structure of Δ9-THC
A
7
Q
What does an octanol:water partition coefficient equal to 1 mean?
A
- then it would be equally well dissolved in both water (hydrophilic) and octanol (lipophilic)
8
Q
What are the octanol:water coefficients for ethanol and Δ9-THC
A
9
Q
Compare and contrast the octanol:water partition coeffient of ethanol and Δ9-THC and how this affects its properties
A
- With regard to ethanol and Δ9- THC you have two compounds at either end of the spectrum
- i.e. one that is particularly water soluble and one that is extremely lipid soluble.
- Clearly, Δ9- THC will have no problems crossing lipid membranes and accessing tissues.
- What about ethanol? Basically, most lipid membranes are slightly permeable to small uncharged polar molecules like ethanol but impermeable to large uncharged polar molecules like glucose.
- As a result, ethanol can diffuse across lipid membranes and access tissues despite being very water soluble.
- Of course, ethanol is also small enough to diffuse through aqueous pores in the membrane – therefore there are several routes by which ethanol can access tissues.
10
Q
Why is there incredibly clear information on dosing for alcohol?
A
- Alcohol is also fairly unique among drugs in that you can access pretty clear information on how to determine the bioavailability of the drug i.e. the blood levels of the drug.
11
Q
How do you calculate the amount of alcohol in any drink you consume?
A
- we need to know the alcohol by volume (ABV) and the actual volume consumed
- ABV x 0.78 x volume consumed per 100 ml
- For simplicity, the UK uses the unit system, which is a lot easier to calculate and understand. For this calculation, you simply use the following;
- ABV x volume (ml)/1000
12
Q
Calculate the absolute amount of alcohol and its units
A
13
Q
Observe the table of how alcohol dose relates to blood alcohol levels (bioavailability)
A
- This is not as easy to accurately determine and requires certain assumptions to be made.
- However, we can generate a table that provides a rough estimate of how alcohol dose relates to blood alcohol levels (bioavailability)
- If we consider a male who weighs 55 kg.
- If this individual drinks one bottle of beer described above, then they will have consumed 13.65 g of alcohol.
- The dose administered can then be considered as 250 mg/kg body weight.
- This would equate to a blood alcohol level of 50 mg/100 ml of blood.
- If the individual drinks two bottles, then they will have consumed a dose of 500 mg/kg body weight (27.3 g alcohol in 55 kg male).
- This would equate to a blood alcohol concentration of 100 mg/100 ml of blood.
- After one bottle, the dose related effects are regarded as minimal.
- After two bottles, the dose related effects are regarded as sufficient to impair motor function. In the UK, the legal driving limit is 80 mg/100 ml of blood.
14
Q
On the table below, indicate the line that separates blood alcohol levels below the UK legal limit from those values equal or above the UK legal limit
A
15
Q
How accurate is the blood alcohol content (BAC) table?
A
- This table is clearly not perfect – although it is pretty accurate for 95% of the population.
- As you can see from the table, you do need to factor in the rate of alcohol metabolism.
- As more time passes more alcohol is metabolised and the blood alcohol level will drop.
- Some individuals, particularly those considered heavy drinkers, will metabolise the alcohol more quickly i.e. their alcohol tolerance is greater.
- Some individuals have defective alcohol metabolising enzymes and metabolise alcohol more slowly.
16
Q
Why is it difficult obtaining the dose of cannabis?
A
- attempting to determine the dose of cannabis administered is a great deal more difficult.
- For example, some of the milder cannabis cigarettes might contain 10 mg of active tetrahydrocannabinol, whereas the more powerful forms of cannabis (e.g. skunk) might contain 150 mg THC.
- As we will discuss in subsequent sections, even if you know the dose administered, the pharmacokinetics of cannabis make it difficult to determine the dose related effects.
17
Q
Which tissue membrane is it more important for drugs to reach in order to be well absorbed after oral or inhalational administration?
A
- alcohol: small intestine/ileum
- cannabis: alveoli/alveolus
- The plasma membrane for the microvilli of the small intestine or the alveoli are often only 1-200 nm thick and are very closely associated with blood capillaries.
- As a result, any drug molecules that reach the small intestine or alveolar plasma membrane are likely to diffuse across into the bloodstream extremely quickly.
18
Q
What are some factors limiting drug arrival via the inhalation route?
A
- For the inhalational route, it is mainly due to how much drug cannot penetrate far enough into the lungs.
- For most inhaled drugs, approximately 50% of the administered dose actually gets deep enough into the lungs to allow for absorption.
- The remaining 50% might partly be swallowed or more likely, just breathed back out again (or in the case of smoking be destroyed in the process of pyrolysis – heat induced decomposition).
- Of the 50% that reaches the lungs, only a proportion of that will penetrate deeply enough to access the alveoli where the most efficient and rapid absorption occurs.
19
Q
What are some factors limiting drug arrival via the oral route?
A
- For the oral route, the major obstacle is the stomach.
- If the drug is in the stomach, then it cannot access the small intestine microvilli that provide the most effective site for absorption.
- Alcohol is usually taken in liquid form.
- If the stomach is empty, then any liquid tends to promote stomach emptying (little need to digest and physically disperse liquids)
- i.e. the liquid passes straight into the small intestine.
- In contrast, solid food will slow stomach emptying.
- The stomach needs to time to digest and break up solid food.
- As a result, if you drink alcohol on a full stomach, the alcohol will be retained in the stomach – the alcohol will be absorbed far more slowly from the stomach than the small intestine.
- That is why it is often recommended that you drink alcohol after a meal – it will slow the absorption of alcohol into your blood and reduce your blood alcohol levels.
20
Q
What is the caveat of orally administered drugs (e.g. alcohol) that prevents them from accessing all tissues in the body?
A
- alcohol must first pass through the liver and potentially undergo significant metabolism
26
Q
Describe tissue localisation of alcohol
A
- We have already stated that alcohol has a very low octanol:water partition coefficient
- this means that alcohol is relatively water soluble and is therefore going to be preferentially distributed to tissues with a high water content.
- using the relative water content for the four tissues, you can see that alcohol prefers to exist within the blood plasma than the brain since blood plasma has the higher water content.
- However, this is not to say that alcohol does not distribute to the brain from the plasma.
- Firstly, the brain still has a high water content and secondly the brain has a very high regional blood flow.
- Drug distribution of alcohol between the blood and brain at equilibrium:
- When the alcohol concentration is high in the blood, there will be a concentration gradient that drives alcohol out of the blood into the brain.
- Once an equilibrium is reached, there will tend to be a higher concentration of alcohol in the blood due to the higher water content
- see figure
27
Q
Discuss the tissue localisation of cannabis
A
- the fact that cannabis has a very high octanol:water partition coefficient means that cannabis is going to be preferentially distributed to tissues with a high fat content.
- Drug distribution of Δ9-THC between the blood and brain at equilibrium:
- Comparing the distribution of cannabis (Δ9-THC) between the blood and the brain, and in contrast to alcohol, cannabis will tend to be at a higher concentration in the brain than in the blood at equilibrium (see figure on left).
- So far, we have compared distribution to the brain, a tissue with a very high blood flow.
- What about the adipose tissue, which has a very low blood flow (approx. 2% of cardiac output).
- Clearly for alcohol, only a small percentage of the alcohol would be delivered to the adipose tissue, and at equilibrium the alcohol would be distributed hugely towards the blood plasma.
- In contrast, despite low blood flow to the adipose tissue, cannabis (Δ9-THC) would still accumulate in the adipose tissue due to high lipid solubility of the drug.
28
Q
Can you rank these individuals in terms of their relative sensitivity to alcohol and cannabis?
A
- the non obese male was the least sensitive to alcohol.
- The non-obese male possessed the highest percentage of body water (which includes the blood plasma).
- At a very basic level, this means that alcohol is more diluted in the non-obese male, and as a result has less of an overall effect – remember everything in pharmacology is dose related.
- This is one of the reasons why women tend to be more sensitive to the effects of alcohol than men – they have less body water, so the alcohol is more concentrated in their body water and therefore has a more powerful effect.
- In contrast, the non-obese male was the most sensitive to the effects of cannabis.
- In the non-obese female and the obese male, there is more body fat which will absorb a greater percentage of the cannabis dose.
- As a result, less cannabis will be available in the blood to produce an effect.
30
Q
How many steps is the phase 1 metabolism of ethanol and Δ9-THC?
A
- for both it is a two step process
31
Q
What type of reactions occurred during the phase 1 metabolism of ethanol and Δ9-THC?
A
- all oxidation, except the metabolism of Δ9-THC, which is hydroxylation
33
Q
What is generated after phase 2 metabolism of cannabis and why?
A
- a glucuronide
- effective excretion of cannabis is going to require Phase 2 metabolism to generate a far more water soluble conjugate
39
Q
What is the active metabolite of ethanol?
A
- acetaldehyde
- rather than contributing to the desired effects of alcohol, acetaldehyde seems to be largely responsible for the side effects associated with alcohol.
- Genetic polymorphisms in the aldehyde dehydrogenase gene (very common in Asian populations) can lead to a build up of acetaldehyde (due to poor acetaldehyde metabolism), which is associated with nausea (gastric irritation), flushing (peripheral vasodilation) and headaches (central vasodilation).
40
Q
Describe the active metabolite of cannabis
A
- 11OH-THC
- this ‘active’ metabolite is believed to be more potent than Δ9-THC.
- We have already mentioned the fact that this metabolite would retain a high degree of lipid solubility.
- As a result, the known effects of cannabis can be attributed to both Δ9-THC and 11OH-THC i.e. the ‘active’ metabolite must be responsible for some effects.
41
Q
Describe the drug target for cannabis
A
- the cannabinoid receptor
- The cannabinoid receptor is a G-protein coupled receptor that is negatively coupled to adenylate cyclase
- i.e. it decreases the activity of this enzyme.
- As a result, activation of this receptor would tend to lead to decreased cellular activity within that cell due to decreased adenylate cyclase activity – a classical depressant effect.
- There are several endogenous agonists for this receptor, but the most common is anandamide.
- Δ9-THC (and other cannabinoids) are also agonists for this receptor (albeit less potent).
42
Q
What is the drug target for alcohol?
A
- As for alcohol, this is a more difficult question to answer.
- If you consider the lock and key hypothesis mentioned in session 1, alcohol is a very simple molecule and as a result will fit in a number of different locks.
- However, for each of these locks, alcohol is not a great fit.
- As a result, alcohol does not have a specific target. It can induce weak effects on a number of different targets.
- The figure below demonstrates alcohol binding to the opioid receptor – as you can see, there a number of potential binding sites on the opioid receptor.
- Alcohol can loosely bind to one of them (NOTE – we will revisit this receptor in the session on opioids. At this point you will realise that a potent agonist would need to interact with all of the available binding sites)
43
Q
The table below provides three other known targets for alcohol. Can you determine whether alcohol would increase or decrease the activation of these targets?
A
- In order for alcohol to induce a depressant effect, it would need to either increase an inhibitory factor (e.g. GABAA receptor) or decrease an excitatory factor (e.g. NMDA receptor or Ca2+ channels).
46
Q
Discuss the memory loss associated with cannabis and alcohol
A
- The dentate gyrus within the hippocampus is vital for the formation of memory (see image below).
- We know that activation of cannabinoid receptors on mitochondria within the dentate gyrus can lead to impaired memory formation.
- Due to the lack of selectivity of alcohol, it would be a lot more difficult to pinpoint the specific target that mediated this effect for alcohol.
50
Q
Describe alcohol-induced liver disease
A
- As described above, alcohol is metabolized by alcohol dehyrdrogenase and aldehyde dehydrogenase.
- Both of these enzynmes use NAD+ as a cofactor, which produces NADH.
- NADH impairs β-oxidation of fatty acids which leads to alcoholic fatty liver. - As described above, the cytochrome P450 system is upregulated during chronic alcohol intake.
- This system leaks oxygen radicals.
- If the production of these oxygen radicals exceeds the cellular defence then oxidative stress leads to mitochondrial damage and inflammation. - As described above, acetaldehyde is a toxic metabolite of alcohol.
- Excessive acetaldehyde decreases activity of key metabolic enzymes and also promotes hepatocyte cell death. - A vicous cycle is produced. Mitochondrial damage, cell death and inflammation result in hepatitis.
- Eventually, fibroblasts infiltrate and replace lost hepatocytes with connective tissue which further reduces the metabolic capacity of the liver (cirrhosis).
51
Q
What is the major toxic effect associated with cannabis use?
Describe it
A
- The major toxic effect associated with cannabis use is psychosis.
- The link between cannabis use and psychosis is less easy to demonstrate and explain.
- However, there is one region of the brain that has been implicated – the anterior cingulate cortex (as highlighted in the MRI scan below)
- One of the roles of this part of the brain is to do with performance monitoring and the adjustment of behaviour in order to avoid losses.
- In changing environments we constantly need to adapt our behaviour by detecting and focusing on the goal-relevant information and selecting the most appropriate behaviour.
- For example, consider the ability to drive a car while simultaneously engaging in a discussion with a passenger.
- If we enter a narrow mountain road and a heavy storm breaks out, we might feel the need to discontinue our conversation in order to better focus our cognitive resources on safe driving.
- One part of psychosis is an inability to display appropriate behaviour within a given context.
- The suggestion is that cannabis has a depressant effect in this region of the brain, and in extreme cases this can lead to psychosis.
