pharmacokinetics

Question 1

what’s pharmacokinetics all about?

Answer 1

What a body does to a drug
This can vary between people, for example from different ethnic groups
Key principles:
ADME - Absorption, Distribution, Metabolism, Excretion
REMEMBER - no matter how selective, any drug, if the concentration is high enough, will interact with many other proteins

Question 2

what is bulk flow?

Answer 2

this is how most drugs travel i.e. in the plasma

Drugs differ in how they get into and out of the plasma

Question 3

what are four ways of drugs being absorbed (travelling across a plasma membrane)?

Answer 3

1. diffusion - most common - drug must be lipophilic
2. ion channels - very few drugs are small enough
3. carriers - for large molecules. as A.a and glucose transporters are very specific, drugs typically use carriers evolved to remove toxins in places like the gut, BB barrier or kidney

pinocytosis - membrane invaginates and scoops up some extracellular stuff to take it into the cell. Transcytosis can then occur, where an internalised pinocytic vesicle can go across the cell, fuse with membrane and release contents. Example - getting insulin or antibodies across the BB barrier

Question 4

what three things does absorption depend on and what are they?

Answer 4

Lipid solubility -
VERY important, defined by a constant known as the partition coefficient
This describes how readily something dissolves in water vs oil

Diffusivity - dependent on diffusion coefficient and conc. grad, dependent on molecular weight (MW, bigger = slower)

Polarity - charge = repulsion
Non polar drugs dissolve easily in lipids, so have a high rate of absorption at gut, they also show high increased renal elimination as they pass across barriers easily, and also have high penetration into tissues and BB barrier

also consider site/method of absorption

Question 5

why is the pH of a drug’s environment so important?

include an example

Answer 5

most drugs are weak acids or weak bases
we need to know how much of a drug administered will be in its dissociated/charged form or not, which is entirely dependent on pH. being dissociated, and therefore charged, or not decides whether these drugs are absorbed/move across membranes…

Question 6

at what kind of pH are weak acids typically NOT dissociated/charged?

Answer 6

weak acids will be un-ionised at low pHs because lots of H+ present drives the equilibrium the other way. This is what we want - uncharged can cross lipid membranes

Question 7

what equation can tell us how much of a drug is dissociated at a certain pH?

Answer 7

Henderson-Hasselbach equation

pH = pKa + log( [A-] / [HA] )

Question 8

using an example, explain what ion trapping is

Answer 8

Aspirin as an example:
A weak acid, so a low pKa of 3.5
This means in the stomach where pH is 3ish, lots of H+ already so aspirin is mostly unionised and therefore moves out of the stomach very quickly.

Plasma now has much higher pH of 7.4, using H.H equation we see almost 1000 times more of the aspirin is in ion form, which means, once in the plasma, these ions are trapped, known as ‘ion trapping’ as charged molecules cannot cross the lipid

At the kidney, in the urine pH is higher at 8, so more dissociate, ions are very well trapped in urine and can be excreted

Question 9

what kind of medications can prolong a drug’s effects?

specifically weak acids

Answer 9

medications that cause urinary acidification can slow down excretion of weak acid drugs, prolonging their effects

some medical conditions can cause this

Question 10

how can ion trapping be used when treating accidental poisoning?

Answer 10

Knowledge of pH can be used when someone has taken to much of a drug that may be a weak acid
Increasing plasma pH would mean greater trapping of a weak acid in its ionic form, so that it cannot enter other organs and the rate of its excretion will rise

Question 11

methods of administration - what are they used for/benefits/drawbacks? (x7)

Answer 11

Intravenous route -
Fastest and most reliable, so is used in emergencies as it is not the most comfortable/home accessible way

Intramuscular/subcutaneous injections -
Next fastest, avoids digestive system so if molecules are proteins this is useful, site of injection effects absorption as blood flow varies

Intrathecal injection -
Lumbar puncture used to produce regional anaesthesia, useful for CNS, like in childbirth

Inhalational administration -
Localised to lung, or drug molecule is a gas (can still reach plasma as lungs are well perfused)

Percutaneous administration -
Directly through the skin, still avoids gut metabolism, but enters plasma slowly and different between patients, tho slow can actually be desirable. Obviously also used for skin issues

Oral administration -
Easiest and most common, most absorption occurs in the gut
pH, food in the gut that may interact with the drug, size of the particle
Also consider portal system connecting the gut to liver, main site of metabolism, so lots of the drug may go straight to the liver to be broken down and excreted without reaching the plasma for bulk flow.
A person may also have issues with their gut - vomiting would be a problem.

Rectal route -
avoids this issue tho is not very comfortable

Question 12

define bioavailabilty

Answer 12

the fraction of the ingested dose that makes its way to the plasma

Question 13

what are the two options for carrier mediated transport?

Answer 13

for large drugs…

active - using ATP/ABC transporters

passive - using SLC (solute carriers) transporters

Question 14

name 5 sites where SLCs are commonly expressed and are important for carrier-mediated

Answer 14

the blood–brain barrier
the gastrointestinal tract
the renal tubule
the biliary tract
the placenta

Question 15

is metformin as effective for everyone with diabetes?

Answer 15

no, the OCT1 transporter involved can have a polymorphism meaning people can respond differently

Question 16

distribution - what are the body’s four major components?

Answer 16

1. Extracellular fluids -
   plasma 4.5% body weight
   Interstitial fluid 16%
   Lymph 1-2%
2. Intracellular fluids - 30-40%
3. Transcellular fluids (e.g. CSF) - 2.5%
4. Fat - 20% roughly

Question 17

what is ‘volume of distribution?

Answer 17

Defined as a measure of the volume of fluid that would be required to hold the amount of drug in the body as measured in the plasma

Vd = dose / Cp

Cp = concentration of drug in the plasma

Question 18

explain the relationship between Vd and Cp

Answer 18

You give 500mg of paracetamol, then measure the conc. In the plasma.
Vd is how much volume of fluid you would need to achieve this concentration, so a high CP would mean Vd is low
If Vd is high, the Cp is low, so this tells us a drug can move/distribute very easily between the fluid compartments of the body

Question 19

heparin has a small Vd - what does this tell us?

Answer 19

meaning it gets trapped in the plasma (tho another reason for this is that heparin gets trapped by plasma proteins)

Question 20

what is the blood-brain barrier?

how can it be crossed?

Answer 20

BB barrier = endothelial cells with very tight junctions impermeable to water soluble molecules

Diffusion, so must be lipophilic/non-polar
for large molecules, a carrier able to take it across the plasma membrane is needed

Question 20

tight junctions in the BB barrier can break down. in what situation does this often happen and how can we use this?

Answer 20

during inflammation

We can take advantage of this, for example with brain infections, antibiotics normally cannot cross the BB barrier. Tho the infection can cause inflammation that results in these tight junctions becoming permeable, and antibiotics should be able to cross

Question 21

what is the effect of drugs binding to plasma proteins on dose increase?

Answer 21

(note - most common protein is albumin, likes to bind to weak acids)

binding to plasma proteins originally limits free drug concentration
as you increase the dose the plasma proteins will become saturated, increasing dose from this point causes a big jump in plasma concentration of the drug (free)

this means the therapeutic window is small (and slows elimination)

Question 22

how is body fat important when considering dosage?

Answer 22

Higher body fat - drug also distributed into body fat (lipids) which then acts as a reservoir of the drug and it stays in the body for longer, and is diluted

Low body fat = lipophilic drug will mostly go straight across plasma membranes and will be eliminated quickly

dose may need to be adjusted accordingly

Question 23

what are the two phases of drug metabolism?

Answer 23

Phase 1 - catabolic reactions

These often produce a more ‘active’ compound, which in cases like paracetamol is quite toxic, though is very short lived and quickly enters the second phase of metabolism

Phase 2 - synthetic anabolic reactions
These involve ‘conjugation’ of the active compound from phase 1 with larger molecules in order to produce an inactive, excretable product

Question 24

where does metabolism of drugs occur and what machinery is commonly used?

Answer 24

Occurs within hepatocytes so drug must be able to enter the cell somehow
Uses a class of enzymes known as ‘microsomal’ enzymes, some common subtypes are the cytochrome P450 family, or alcohol dehydrogenase, or MAO (monoamine oxidases)

Question 25

how can some drugs affect their own, or another drug’s metabolism?

Answer 25

some drugs may affect the metabolism of themselves or of other, unrelated drugs, via enzyme induction (an increase in the rate of hepatic metabolism, mediated by increased transcription of mRNA encoding the genes for drug-metabolising enzymes)

Question 26

explain how aspirin is metabolised and eliminated

Answer 26

Phase 1 - hydroxylation of the acetyl group to form salicylic acid, the reactive intermediate

Phase 2 - the new hydroxyl bonds with a large glucuronide molecule, so its now too big/changed so much it is inactive, and will re-enter the plasma, move via bulk flow, enter the kidneys and be excreted in the urine

Question 27

how many P450 enzymes are there and which work on which drug?

Answer 27

Humane genome project identified 57 genes that code for P450 enzymes

Which enzymes for which drugs? -
Each enzyme works to metabolise multiple drugs
This is dependent on the chemical structure/properties of the drug, not it’s pharmacological effects, for example paracetamol and ibuprofen are metabolised by different P450 enzymes

Question 28

what are P450 inducers, including some examples found in diet?

Answer 28

Inducers of P450 enzymes will increase the metabolism of a drug
They can be so effective sometimes that they lower the concentration of a drug so that its therapeutic effects are noticeably lessened

Examples include compounds in brussel sprouts, broccoli and tobacco (nicotine) for the enzyme that metabolises caffeine and paracetamol (acetaminophen)

Question 29

P450 inhibitors - give an example

Answer 29

Some compounds from people’s environments can inhibit certain isoforms of P450 enzymes, meaning they won’t be metabolised as quickly and can reach toxic concentrations. Grapefruit juice cannot be taken with certain cardiac medicines, including the blood thinner warfarin

Question 30

why is conjugation with larger molecules so important for excreting lipophilic drugs?

Answer 30

they normally cross membranes so well that, as they are, they are not well eliminated by the kidneys

Question 31

what are the three methods of renal excretion and when are they used?

Answer 31

Glomerular filtration -
works very well for conjugated drugs with Mol.Weight < 20 Kdaltons
If a drug is bound to plasma, albumin already exceeds this weight, so it won’t be removed by glomerular filtration

Active tubular secretion -
Requires OCT and OAT (cation and anion transporters)
They actively secrete these conjugated drugs, as well as the weak acid and weak base drugs even before metabolism (as they are cations and anions)

Passive diffusion - through tubular epithelia
Very inefficient, can be done by some lipophilic drugs

Question 32

why does the dose for penicillin need to be quite high?

Answer 32

its excretion via organic anion transporters is so effective that it gets removed too quickly

Question 33

why does diazepam act for so long?

Answer 33

Diazepam is lipophilic (needed to cross BB barrier) but is therefore hard to excrete using this inefficient passive diffusion. When in the liver, it is metabolised to form a second metabolite that is still active AND lipophilic, extending action to almost 48hrs

Question 34

treating a patient with renal disease?

Answer 34

Renal disease - Impacts drug clearance so must be taken into account when prescribing drugs, toxicity could occur

Question 35

aside form renal excretion, what are some other methods of excretion?

Answer 35

GI excretion (portal system - bile - back to gut - excreted as faeces)
Lung excretion - breathed back out when a drug is inhaled

sweat, or breast milk

Question 36

why is predicting a drug’s time course so important?
what is ‘t 1/2’ ?

Answer 36

it underpins the dosing regime

t 1/2 is essentially a drug’s half life - the time taken for plasma concentration of a drug to half

Question 37

explain a drug’s time course using a single-compartment model

Answer 37

Drug is distributed into one homogenous compartment eg. Following intravenous injection….and then is ‘cleared’ by combinatation of metabolism and excretion

In such a situation the concentration of the drug in the plasma follows ‘first-order’ kinetics, where rate of elimination is directly proportional to drug concentration.

Plasma half life is the same irrespective of drug concentration and can be easily calculated and only depends on the rate of elimination (a constant)

Question 38

what happens when you give continuous/repeated doses of a drug?

hoe does this vary between dosing method?

Answer 38

(for an IV) rate of infusion of a drug is eventually matched by rate of excretion and a ‘steady state’ is reached

With repeated doses (so not IV), steady state is reached at roughly the same time as IV, but shows more fluctuations in getting there. Note that time it takes to reach steady state is the same no matter the route/method of administration, but number of doses needed to reach steady state DO vary with dosing regime

Question 39

typically, when is a steady state reached?

Answer 39

usually within 3.5 half lives of a drug

Question 40

is a single-compartment model accurate?

Answer 40

no -
In reality drugs rarely behave this way, as they distribute among different compartments and so it is much more difficult to predict drug concentrations

Question 41

what are saturating kinetics and how do they differ from ‘normal kinetics’?

Answer 41

normal = first order kinetics, increase in dose causes a proportional increase in steady-state plasma concentration

saturating = zero order kinetics:
when the metabolism of the drug or transporters for the drug cause saturation
A small increase in dosage results in a disproportionate increase in steady state plasma concentration which can lead to toxicity
The systems involved in the elimination of the drug gets overwhelmed (happens with alcohol, alcohol dehydrogenase needs a cofactor that is in limited amount)