Pharmacokinetics

Pharmacokinetics is the study of what the body does to a drug.
Pharmacodynamics is the study of what a drug does to the body.
Routes of Drug Administration:
Intravenous
Oral
Buccal
Sublingual
Rectal
Intramuscular
Transdermal
Subcutaneous
Inhalational
Topical
Of all of these routes you are most likely to be asked about the transdermal, as it is fashionable.
Otherwise, most other basic pharmacology questions tend to concern the pharmacology of intravenous agents; that is what is discussed below.
First Order Kinetics:
A constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is proportional to the amount of drug in the body. The majority of drugs are eliminated in this way.

What follows concerns drugs which follow first order kinetics.

The Volume of Distribution (Vd) is the amount of drug in the body divided by the concentration in the blood. Drugs that are highly lipid soluble, such as digoxin, have a very high volume of distribution (500 litres). Drugs which are lipid insoluble, such as neuromuscular blockers, remain in the blood, and have a low Vd.
The Clearance (Cl) of a drug is the volume of plasma from which the drug is completely removed per unit time. The amount eliminated is proportional to the concentration of the drug in the blood.
The fraction of the drug in the body eliminated per unit time is determined by the elimination constant (kel). This is represented by the slope of the line of the log plasma concentration versus time.
Cl = kel x Vd
Rate of elimination = clearance x concentration in the blood.
Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 4 half lives, elimination is 94% complete.
It can be shown that the kel = the log of 2 divided by the t1/2 = 0.693/t1/2.
Likewise, Cl = kel x Vd, so, Cl = 0.693Vd/t1/2.
And t1/2 = 0.693 x Vd / cl
The rate of elimination is the clearance times the concentration in the plasma
Roe = Cl x Cp
Fraction of the total drug removed per unit time = Cl/Vd.
If the volume of distribution is increased, then the kel will decrease, the t1/2 will increase, but the clearance won't change.
Confused?
Example: You have a 10ml container of orange squash. You put this into a litre (ok 990ml!) of water. The Vd of the orange squash is 1000ml. If, each minute, you empty 10ml of the orange liquid into the 10ml container, discard this, and replace it with 10ml of water. The clearance is 10 ml per minute. The elimination half life is: 70 minutes . The kel is Cl/Vd = 10/1000 = 0.01. Shown the other way, 0.693/50 = 0.01.
If the volume of the container is increased to 2000ml, then the clearance remains the same, but the Vd, and consequently the t1/2, increases (to 140 minutes).
Simple, isn't it?
What is described above is a single compartment model, what would occur if the bloodstream was the only compartment in the body (or if the Vd = the blood volume). But the human body is more complex than this: there are many compartments: muscle, fat, brain tissue etc. In order to describe this, we use multicompartment models.
Multicompartment Models:
Why does a patient wake up after 5 minutes after an injection of thiopentone when we know that it takes several hours to eliminate this drug from the body? What happens is that, initially the drug is all in the blood and this blood goes to "vessel rich" organs; principally the brain. After a few minutes the drug starts to venture off into other tissues (fat, muscle etc) it redistributes, the concentration in the brain decreases and the patient wakes up! The drug thus redistributes into other compartments.
If you were to represent this phenomenon graphically, you would follow a picture of rapid fall in blood concentration, a plateau, and then a slower gradual fall. The first part is the rapid redistribution phase, the alpha phase, the plateau is the equilibrium phase (where blood concentration = tissue concentration), and the slower phase, the beta phase, is the elimination phase where blood and tissue concentrations fall in tandem. This is a simple two compartment model and is as much as you need to know.

An couple of interesting pieces of information can be derived from the log concentration versus time graph. If you extrapolate back the elimination line to the y axis, then you get to a point called the CP0 - a theoretical point representing the concentration that would have existed at the start if the dose had been instantly distributed (dose/Vd). From this new straight line you can figure out how long it takes for the concentration to drop by 50%: the elimination half life. Likewise, a similar procedure can be performed on the α phase: the redistribution half life.
While it is very important that you understand these concepts, the reality is that most drugs are infinitely more complicated that this, and computer calculations are required to derive this data.
Bioavailability
This is the fraction of the administered dose that reaches the systemic circulation. Bioavailability is 100% for intravenous injection. It varies for other routes depending on incomplete absorption, first pass hepatic metabolism etc. Thus one plots plasma concentration against time, and the bioavailability is the area under the curve.
Zero Order Elimination
Why if I have 10 pints of beer before midnight will I fail a breathalyser test at 8 am the following morning? Either this is due to alcohol having a very long half life (which it does not) or that alcohol is cleared in a different way.
What happens is that the metabolic pathways responsible for alcohol metabolism are rapidly saturated and that clearance is determined by how fast these pathways can work. The metabolic pathways work to their limit. This is known as zero order kinetics: a constant amount of drug is eliminated per unit time. This form of kinetics occours with several important drugs at high dosage concentrations: phenytoin, salicylates, theophylline, and thiopentone (at very large doses). Because high dose thio is very slow to clear, we no longer use it in infusion for status epilepticus (as it takes ages for the patient to wake up!).
Dosage regimens
The strategy for treating patients with drugs is to give sufficient amounts that the required theraputic effect arises, but not a toxic dose.
The maintenance dose is equal to the rate of elimination at steady state (i.e.at steady state, rate of elimination = rate of administration):
Dosing rate = clearance x desired plasma concentration.
Drugs will accumulate within the body if the drug has not been fully eliminated before the next dose. Steady state concentration is thus arrived at after four half lives. This is all very well if you are willing to wait 4 half lives for the drug to be fully effective, but what if you are not? What you may need to do is to "load" the volume of distribution with the drug to achieve target plasma concentrations rapidly: the loading dose.
The loading dose = the volume of distribution x the desired concentration (i.e. the concentration at steady state).
You can figure this out by: Loading dose = usual maintenance dose / usual dosage interval x kel (t1/2/0.693).
Hepatic Drug Clearance
Many drugs are extensively metabolised by the liver. The rate of elimination depends on 1) The liver's inherent ability to metabolise the drug, 2) the amount of drug presented to the liver for metabolism. This is important because drugs administered orally are delivered from the gut to the portal vein to the liver: the liver gobbles up a varying chunk of the administered drug (pre-systemic elimination) and less is available to the body for theraputic effect. This is why you have to give a higher dose of morphine, for examole, orally, than intravenously.
Hepatic drug clearance (i.e. the amount of each drug gobbled up by the liver) depends on:
1) The Intrinsic clearance (Cl int).
2) Hepatic blood flow.
These two factors are independent of one another, and their combined effect is the proportion of drug gobbled up: the extraction ratio.
For drugs that have a low intrinsic clearance, this effect can be increased by giving a second agent that boosts the effect of the liver's enzyme system; these are enzyme inducers. Examples of such drugs are cigarrettes, antiepileptics (carbamazepine & phenytoin), rifampicin, griseofulvin, alcohol and spironolactone (CAR GAS) [also barbiturates]. Consequnetly if a drug addict is given rifampicin or tuberculosis, a higher dose of heroin is required for the same effect. Enzyme inhibitors have the opposite effect: examples are flagyl, allopurinol, cimetidine, erythromycin, dextropropoxyphene, imipramine, (the) pill (FACE DIP).
Likewise, if the blood flow increases, the liver has less chance to gobble up the drug, and the extraction ratio falls. This is particularly the case, as you would expect, of the intrinsic clearance is low.
Illustration: Think of factory workers picking bad apples out of a pile on a conveyor belt, if only one person (low intrinsic clearance) is doing the picking and the speed of the conveyor belt is increased, more bad apples get through. If there are several pickers (high intrinsic clearance) then they are much more able to cope with an increase in the speed of the conveyor belt, but there will come a rate at which they will become overwhelmed, and bad apples will get through.
From this example you can take home this message: for drugs with a low extraction ratio, the kinetics (the body's ability to deal with the drug) depends on enzymatic activity (giving an enzyme inducer effectively gives the single picker 4 arms!). For high extraction ratio drugs, kinetics depends on liver blood flow - the slower the flow the higher the extraction, the higher the flow the lower the extraction ratio.
Drug distribution
When a drug is introduced into the body, where it ends up depends on a number of factors:
1) blood flow, tissues with the highest blood flow receive the drug first, 2) protein binding, drugs stuck to plasma proteins are crippled, they can only go where the proteins go (and that's not very far!), 3) lipid solubility and the degree of ionisation, this describes the ability of drugs to enter tissues (highly lipid soluble / unionised drugs can basically go anywhere).
Protein Binding
Most drugs bind to proteins, either albumin or alpha-1 acid glycoprotein (AAG), to a greater or lesser extent. Drugs prefer to be free, it is in this state that they can travel throughout the body, in and out of tissues and have their biological effect. The downside of this is that they are easy prey for metabolising enzymes.
As you would expect, more highly bound drugs have a longer duration of action and a lower volume of distribution. Generally high extraction ratio drugs' clearance is high because of low protein binding and, conversely, low extraction ratio drugs' clearance is strongly dependent on the amount of protein binding.
Why is this important? If a drug is highly protein bound, you need to give loads of it to get a theraputic effect; as so much is stuck to protein. But what happens if another agent comes along and starts to compete with the drug for the binding site on the protein? Yes, you guessed it, the amount of free drug is increased. This is really important for drugs that are highly protein bound: if a drug is 97% bound to albumin and there is a 3% reduction in binding (displaced by another drug), then the free drug concentration doubles; if a drug is 70% bound and there is a 3% reduction in binding, this will make little difference.
The drugs that you really need to keep an eye on are: warfarin, diazepam, propranolol and phenytoin. For example, a patient on warfarin is admitted with seizures, you treat the patient with phenytoin, next thing you know - his INR is 10.
The amount of albumin does not appear to be hugely relavent. In disease states such as sepsis, the serum albumin drops drastically, but the free drug concentration does not appear to increase
Degree of ionisation
This is really important with regard to local anaesthetics. The essential fact to know is that highly ionized drugs cannnot cross lipid membranes (basically they can't go anywhere) and unionised drugs can cross freely. Morphine is highly ionised, fentanyl is the opposite. Consequently the latter has a faster onset of action. The degree of ionisation depends on the pKa of the drug and the pH of the local environment. The pKa is the the pH at which the drug is 50% ionised. Most drugs are either weak acids or weak bases. Acids are most highly ionised at a high pH (i.e. in an alkaline environment). Bases are most highly ionised in an acidic environment (low pH). For a weak acid, the more acidic the environment, the less ionised the drug, and the more easily it crosses lipid membranes. If you take this acid, at pKa it is 50% ionised, if you add 2 pH points to this (more alkaline), it becomes 90% ionised, if you reduce the pH (more acidic) by two units, it becomes 10% ionised. Weak bases have the opposite effect.
Local anaesthetics are weak bases: the closer the pKa of the local anaesthetic to the local tissue pH, the more unionised the drug is. That is why lignocaine(pKa 7.7) has a faster onset of action than bupivicaine (pKa 8.3). If the local tissues are alkalinised (e.g. by adding bicarbonate to the local anaesthetic), then the tisssue pH is brought closer to the pKa, and the onset of action is hastened.