Lecture 2 - Pharmacokinetics

Question 1

Define ‘harm rating’

Answer 1

Total measure of a drug’s harmful effects to the user and others used to establish it’s legal classification
in the UK.

Question 2

What is pharmacology?

Answer 2

“The branch of medicine that deals with the uses, effects, and modes of actions of drugs”.

Question 3

What is pharmacokinetics?

Answer 3

Subfield of pharmacology dealing with: “the
absorption, distribution, biotransformation
and excretion of drugs”.

Question 4

What is involved in pharmacokinetics?

Answer 4

• Drug has to be absorbed, and there are factors that affected this.
• Mechanisms are involved that break down and secrete drugs
• Once drugs are metabolised, they are excreted, e.g. through the kidneys, the lungs, sweating etc. Dynamic process – where take drug have absorbing phase until hit maximum point, where begin going to elimination phase
• These factors determine how much of the drug gets to the brain, how fast it gets there, and how long it stays there. The faster the drug gets to the brain, the more likely they are to be abused
• The concentration of the drug is continuously varying because of all these processes – dynamic process
• There are different effects depending on the phase, e.g. absorption phase and elimination phase, even though they have the same drug concentration level.

Question 5

What are factors affecting absorption?

Answer 5

1. Drug solubility - how easy is it for the drug to diffuse across membranes?
2. Ionisation - the more charged a molecule is, the less lipid soluble it is
3. Blood circulation at the site of administration
4. Surface area of the absorbing surface, e.g. muscle.
   The last 2 factors are determined by “route of administration” (oral, intravenous, inhalation, etc.)

Question 6

What are routes of administration?

Answer 6

Oral (peroral or PO, absorption through gastrointestinal tract, not mouth). Most common is taking drugs orally. Absorption through upper or lower intestines. Not invasive, but when take drug orally they are passed through the liver, and immediately metabolised – this creates a lack of control over dose you’re given, but also makes it safe, as the rate at which the drug is metabolised is proportional to the dose of drug going in. 1st pass metabolism – liver acts as safety mechanism.

Question 7

What is an example of first pass metabolism?

Answer 7

Lisdexamfetamine (Vyvanse) - D-ampetamine coupled to amino acid L-lysine (inactive): as metabolised the amino acid is cleaved off, leaving active amphetamine. Result is similar to an extended-release formulation of amphetamine. Stimulant used for ADHD therapy.

Question 8

What is an example of first pass metabolism?

Answer 8

Lisdexamfetamine (Vyvanse) - D-ampetamine coupled to amino acid L-lysine (inactive): as metabolised the amino acid is cleaved off, leaving active amphetamine. Result is similar to an extended-release formulation of amphetamine. Stimulant used for ADHD therapy. Reduces absorption of the drug, making it much slower and longer lasting.

Question 9

What are non-invasive routes of administration?

Answer 9

1. Oral (1st pass metabolism)
2. Nasal (insufflation) - absorption is through the mucus membrane of the nose.
3. Sublingual - under the tongue, absorbed through membranes under the tongue
4. Rectal - if cannot take orally e.g. vomiting, problems with breathing.
5. Transdermal - across the skin, very slow way of administering drugs.
6. Pulmonary absorption (inhalation) - very rapid because lungs are highly vascularised, very efficient, large surface area. When take drugs through the lungs, it goes straight to the brain.
   These routes (except 1) avoid 1st pass metabolism.

Question 10

What are invasive (Transdermal/parenteral) routes of administration?

Answer 10

1. Subcutaneous - under the skin
2. Intramuscular - into the muscle (large surface area, highly vascularised)
3. Intravenous - introducing it straight into the circulatory system
4. Epidural - above the dura matter, spinal anaesthesia
5. Intrathecal - into CSF in subarachnoid space, spinal anaesthesia.
6. Intra-arterial - uncommon route, very dangerous. Inject straight into arterial side. E.g. sodium amytal into carotid artery, deduce what each side of the brain does.

Question 11

What are routes of administration mainly used in animals?

Answer 11

1. Intra-Peritoneal (IP) - injected into area with intestines - lots of surface area, easy way to inject drug into animal.
2. Intracranial - straight into the brain for experimental reasons
3. Intra-Cerebro-Ventricular (ICV) - into the ventricles, usually lateral ventricles

Question 12

What are drug concentrations and half-life?

Answer 12

Drug peak concentration and half life vary by route of administration. Half-life = time for plasma drug concentrations to fall to half of peak level. Takes peak effect, determine where you get 50%, giving an idea of how long the drug effect lasts.

Question 13

How is a route of administration chosen?

Answer 13

Depends on whether the objective is a high peak concentration or a steady state (e.g. methadone) To achieve a feeling of rush or euphoria,
drug users prefer a route that gives
highest peak concentration.
‣ For the majority of medical applications,
wish to treat a condition with the
minimum effective concentration, over an
extended period.

Question 14

What is fentanyl?

Answer 14

A highly potent opiate. Transdermal fentanyl (Duragesic © patch) is used to provide a prolonged, steady analgesic effect to relieve serious pain. Sublingual fentanyl (Actiq © - raspberry-flavored fentanyl lollipops) - absorbed through buccal membranes for rapid adjustment of pain levels. Fentanyl is one of the most highly abused substances by medical
personnel (~75% of these abusers are anesthesiologists, who have access). For max. subjective effects, can be smoked or injected IV. Small mistake in the dose can lead to terrible consequences.

Question 15

What are effects of route of administration on rate of absorption? What are the factors?

Answer 15

1. Amount of drug destroyed 1st-pass metabolism (e.g. by stomach and liver enzymes)
2. Blood circulation at the site of administration
3. Surface area available for absorption
4. Binding to inactive sites (depot binding) - can seep out slowly over time
5. Number of cell layers to blood - number of cell layers that the drug has to pass

Question 16

What is involved in drug distribution?

Answer 16

To get to a brain site, drugs typically need to cross membranes (e.g. stomach wall, capillaries). Drug movement across membranes is a key factor influencing the dose available at site of action

Question 17

What happens in movement across membranes?

Answer 17

Simple diffusion is driven solely by concentration gradient. Drugs pass through lipid bi-layers by passive diffusion. Limiting factors are size and shape of drug molecule, and lipid solubility and ionisation (the more ionised a molecule is, the less lipid soluble it is)

Question 18

Why is lipid-solubility of heroin versus morphine critical?

Answer 18

Heroin (taken IV) reaches the brain much faster than morphine. This increased speed is responsible for the greater rush feeling. Compare methadone (fully synthetic drug), codeine, heroin and morphine. Looking at brain concentration, inject rats with drugs and look at concentration after 15 seconds. Essentially the same drug, but differences in lipid solubility - how quickly they get to the brain

Question 19

What determines lipid solubility?

Answer 19

2 things:
1. Is the drug a weak acid or weak base? (most drugs are weak acids or weak bases)
2. Is the solvent an acid or a base - where is it located?
Drugs that are weak acids ionise more in basic (alkaline) environments, and drugs that are weak bases ionise more in acidic environments More ionisation means less lipid soluble, meaning less absorption/diffusion, and less effect.

Question 20

What is the pKa value?

Answer 20

pH of solution in which 50% of drug ionised and 50% not ionised

Question 21

Weak acid/weak base graph

Answer 21

LOOK AT DRAWING OF GRAPH. If have drug and absorb it into acid environment, get lots of ionisation (low effect). If put into basic environment, get little ionisation (high effect). As get closer to the middle of the graph, get more ionisation.

Question 22

What is ion trapping?

Answer 22

Drugs will be absorbed to different extents in different body compartments. This determines where the drug is best absorbed, and can also lead to the concentration of the drug in one compartment (ion trapping). pKa value doesn’t change, but PH value changes based on where it is located. This is why most drugs of abuse are not absorbed through the stomach. As drug moves around it changes the ph, which is called ion trapping.

Question 23

What is ion trapping in aspirin?

Answer 23

Aspirin is a weak acid with a pKa of 3.5. when in stomach (pH 2-3), most aspirin is not ionised and thus lipid soluble. When in intestine (pH 5-6), aspirin more ionised and less lipid soluble (aspirin is thus best absorbed from stomach). In blood (pH 7.4), most aspirin is ionised. Once aspirin diffused from stomach to blood it becomes ‘trapped’ in blood and does not move easily back to the stomach.

Question 24

What is the ‘blood-brain barrier’?

Answer 24

An idea based on the observation that some dyes, given IV, spread everywhere in the body except brain (and CSD). Dyes not going to the brain suggested there was something protecting the brain from invasion. Important to keep the brain environment as stable as possible. Some exceptional brain areas are outside the BBB - area postrema (vomiting centre, detects toxins), and median eminence (allows hypothalamic hormones into blood, these are large so would be difficult to get through)

Question 25

What is the role of the capillaries?

Answer 25

Typical capillary - elsewhere in the body, capillary membranes are ‘leaky’ to allow a wide range of water-soluble (ionised) molecules in-and-out.
Brain capillaries are more selective (protect the brain), however lipid-soluble molecules (such a psychoactive drugs, small molecules) can still passively diffuse through

Question 26

What happens in drug inactivation and elimination?

Answer 26

Inactivation is usually by metabolism, particularly in the liver by microsomal enzymes. Biotransformation mostly produces more ionised molecules, that do not have brain access. These more ionised metabolites instead become trapped in kidney tubules, then excreted in the urine. Other elimination routes are breath, sweat, milk, saliva, faces.

Question 27

What metabolites are inactive?

Answer 27

Once in the brain, heroin is metabolised into morphine. It’s not heroin acting on your brain, it is diacetylmorphine. The large effects of heroin on your brain is mainly heroin, but the difference is that heroin is much more lipid solute - gets to the brain much faster.

Question 28

What does drug metabolism account for?

Answer 28

Accounts for much individual variation. E.g. alcohol (by alcohol dehydrogenase) becomes acetaldehyde, which by aldehyde dehydrogenase becomes acetic acid. Acetic acid is excreted, metabolised into each step until get to acetic acid. Higher levels of alcohol dehydrogenase means much better metabolisers.

Question 29

What are individual differences in alcohol metabolism?

Answer 29

Sex differences - women have lower levels of gastric alcohol dehydrogenase than men - so for a given dose of alcohol, more enters the bloodstream.
Individual adaption - chronic drinkers have higher levels of alcohol dehydrogenase - contributing to tolerance (drink more to get some effect).
Age - older people have less liver function - less ability to metabolise alcohol
Genetics - 50% of persons of Asian descent have a missense polymorphism in the aldehyde dehydrogenase gene - alcohol flush reaction.

Question 30

What is drug “therapy” for alcoholics?

Answer 30

Disulfiram (Antabuse) - blocks aldehyde dehydrogenase. Causes a severely negative reaction to alcohol (nausea, flushing, confusion, visual disturbance, shortness of breath, fainting). Affects the second step, related to hangovers.