4PY019 IDM Pharmacokinetics and Pharmacodynamics Study Guide PDF

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4PY019

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and dynamics Student Study Guide

Facilitators

Required References

Names:

Required:

Dr Colin Brown

This reading pack

([email protected])

Optional:

Dr Waseem Kaialy

Rang, H. P., Dale, M. M., Ritter, J. M., Flower, R. J., & Henderson, G. (2014). Rang & Dale's Pharmacology: with STUDENT CONSULT Online Access. Elsevier Health Sciences.

([email protected])

Learning Outcomes This study pack will provide you with a fundamental knowledge of drug action. This knowledge is required to underpin further study in pharmacological aspects of pharmacy, pharmaceutical science, and pharmacology. On completion of this topic, you should be able to: •

Relate the impact of mode of delivery, physiological and biochemical mechanisms

to the achievement of effective drug levels •

Describe the structure and function of drug targets and their role in

pharmacodynamics •

Relate the action of drugs on biochemical and physiological function to therapeutics

and toxicology •

Apply quantitative methods to the analysis of pharmacokinetic and

pharmacodynamic data

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Pharmacokinetics and Pharmacodynamics

Contents Learning Outcomes.....................................................................................................................1 What is pharmacology................................................................................................................3 Pharmacokinetics........................................................................................................................4 Definition................................................................................................................................4 Pharmacokinetics includes:.....................................................................................................4 Importance..............................................................................................................................4 Administration............................................................................................................................5 Routes of administration.........................................................................................................5 Bioavailability (F).......................................................................................................................8 Measuring the drug in the plasma...............................................................................................9 Half-life (T0.5 ).........................................................................................................................9 Clearance.................................................................................................................................9 Removal of drug from plasma..................................................................................................10 Zero order kinetics................................................................................................................10 Pseudo zero-order kinetics....................................................................................................10 First order kinetics................................................................................................................11 Pharmacokinetics - Distribution...............................................................................................13 Partition co-efficient.............................................................................................................15 Drugs and membranes...............................................................................................................16 Protein binding..........................................................................................................................17 Volume of distribution..............................................................................................................19 Pharmacokinetics – Metabolism and Elimination....................................................................20 Metabolism – Induction and Inhibition.....................................................................................23 Pharmacokinetics – variations in metabolism...........................................................................24 Pharmacodynamics...................................................................................................................24 So, why is all this important?................................................................................................25 Binding Assays......................................................................................................................26 Dose –response curves..........................................................................................................28 Receptor Reserve..................................................................................................................29 Receptor Antagonists............................................................................................................30 Schild Plots and pA2.............................................................................................................32

What is pharmacology Two Greek words

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Pharmacokinetics and Pharmacodynamics

Pharmaco – pertaining to drugs ology – knowledge of The study of the actions of drugs and their metabolites in the body (the study of all aspects of drug action). Classically pharmacology is divided into Pharmacokinetics (what the body does to the drug) and Pharmacodynamics (which is what the drug does to the body). This presentation is the first of two on the effect of the body on drugs.

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Pharmacokinetics and Pharmacodynamics

Pharmacokinetics Definition Pharmaco – pertaining to drugs; Kinetics – movement The study of the time course of drugs and their metabolites in the body What the body does to the drug; or: administration, absorption, distribution, metabolism and excretion; or: A mathematical explanation of drug distribution. Before a drug can affect any of the systems in the body – at whatever level of organisation – then the drug has to enter the body and be distributed around that body so that eventually (hopefully) enough drug has reached the site of action where it has an effect, i.e., the right drug in the right amount in the right place at the right time. Pharmacokinetics includes: Administration – delivery of drug to the body Absorption – movement of drug across membranes Distribution – description of the compartments of the body entered by the drug Metabolism – chemical alteration of the drug Elimination – transfer of the drug from inside the body to the outside Whilst these definitions are self-evident it is important that you are aware of each stage and are familiar with the terms as each refers to important aspects of ensuring that sufficient drug is present, long enough to give the required response. Importance Pharmacokinetics can help to describe: 

Absorption from site of administration



Delivery to the site of action



Elimination from the body



Time to onset of effect



Duration of effect



Accumulation on repeat dosage

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Pharmacokinetics and Pharmacodynamics



Drug interactions



Inter and intra-patient interactions



Pharmacokinetics can be a predictive science that allows us to work out the required dose of a given drug by noting each of these aspects listed.

Administration

Routes of administration The medical profession will exploit every available surface and orifice:•

Oral (plus buccal and sub-lingual)

•

Rectal

•

Skin (topical)

•

Lungs (plus nose)

•

Eye, Ear

•

Urethra

If no convenient orifice is available… they will make one (injection) •

Intramuscular

•

Subcutaneous

•

Intradermal

•

Intraperitoneal

•

Intrathecal

•

Intra-arterial

Although some of these routes for administering may be more popular than others it is important to realise there is a range and that there is often a pharmacokinetic reason for the choice of route. Often, administration by injection is referred to as parenteral administration as it avoids passing through the gastrointestinal tract. If a drug is given enterally – either by the oral or rectal route then it is likely to be absorbed from the intestine and pass to the liver. This is an important site for metabolising drugs so before the drug has been in the body for very long it is quite likely that it has been Page 5 of 33

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Pharmacokinetics and Pharmacodynamics

metabolised to a different form which be less effective. This is a very important effect, referred to as First Pass Metabolism.

Once into the body the drug gets distributed to different places. Whilst there may be some exceptions, the majority of drugs are transported around the body in the blood so we tend to think of the concentration of drug in plasma as a good indication of drug present in the body. After all if it is in the plasma then it will get to all manner of sites. Unless given intravenously drugs must cross membranes to reach systemic circulation The transition of drugs through the membrane barriers is determined by: •

Lipid solubility

•

Area available for absorption

•

Possible specific carriers

•

Amount that reaches the target may also be compromised by “first pass” metabolism

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Pharmacokinetics and Pharmacodynamics

This follows the same rules as any other physiological transport mechanism. So the more lipid soluble the drug and the bigger the surface area available then the drug is likely to cross the membrane barrier more easily.

Oral route is probably the most well used, it allows self medication and drugs can be given in a number of forms – liquid, tablet, capsule. Along with rectal administration the drug enters the intestinal tract. Some drugs can be given just under the tongue so the drug enters into the blood vessels in that area. It is a well vascularised area – remember how easily your tongue bleed if you cut it. Transdermal patches are becoming a very popular way of delivering drugs e.g. nicotine patches. Lungs are a very quick route for drug administration. Think about the narrow divide between the inside of the alveolus and blood capillary. Think also of the large surface area available for exchange. Nasal – a convenient point of entry easily accessed. IM and SC – drug goes into areas near to blood vessels so drug has to pass through smooth muscle and endothelial lining in order to enter the plasma. Page 7 of 33

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Pharmacokinetics and Pharmacodynamics

Intravenous injection is an ideal means of achieving a rapid response as drug arrives virtually immediately into the plasma. As well as the properties listed on the slide – it also demands very sterile conditions and should only be administered by trained personnel. Oral route

Safer and more convenient than injection (absorbed

Buccal/sublingual

by either passive or active transport) Avoids presystemic metabolism

Rectal Transdermal

Useful in patients who are vomiting/unconscious Becoming more popular avoids presystemic

Lungs

metabolism Volatile anaesthetics

Nasal Intramuscular Subcutaneous Intrathecal Intravenous

Useful absorption of some peptides (DDAVP) Useful in emergencies Useful for insulin, heparin administration Directly into central nervous system, very high risk Very useful in emergencies for most rapid and predictable reactions but too rapid an administration is potentially very dangerous as a high concentration can reach the heart.

I.V. Not easily reversed

The difference between IV and oral dosing is illustrated by this graph of the elimination of drug from plasma with time. IV starts high and follows an exponential decay curve as the drug will leave the plasma to go to its target organs and is eventually metabolised and eliminated. An oral dose may not give the same peak in plasma and the time to get to a peak is longer because the drug will have to pass through the GI tract, then go via the hepatic portal vein to the liver where it will experience first pass metabolism.

Bioavailability (F) • Can be used to define how well a drug is absorbed and reaches its site of action •

Usually determined by comparison of oral and IV absorption

F=

amount of drug absorbed in systemic circulation following oral administration amount of drug absorbed when the same dose is administered intravenously Page 8 of 33

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Pharmacokinetics and Pharmacodynamics

This means that less drug tends to be available following an oral dose. There are a number of ways in which bioavailability is interpreted – here we are comparing IV to oral dosing and using the comparison to give the fraction of drug available.

Measuring the drug in the plasma Two important measurements we need to make which give us some idea of the way in which the body is dealing with the drug.

Half-life (T0.5 ) The time it takes for the plasma drug concentration to fall to half its original value. Half-life is particularly important as it gives information on the length of time that a drug will remain in the body.

Clearance

rate of elimination clearance= plasma drug concentration

Removal of drug from plasma Gives information on the behaviour of the drug in the system Zero order kinetics •

Rate of elimination is constant and independent of drug concentration.

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Pharmacokinetics and Pharmacodynamics

•

T0.5 depends on the amount of drug given and is longer when more drug is given

•

Note though that few (if any at all) drugs behave in this way.

As you can see for zero order the plot of plasma concentration Cp with time is a straight line and half-life is directly related to the amount of drug given.

Pseudo zero-order kinetics •

At high concentration the kinetics are zero order whilst at low concentration the kinetics are first order.

•

Ethanol is removed in this way

•

Depends on the pathways for drug metabolism

This is an interesting example of elimination by drugs that seem to show a mix of zero and first order kinetics. This is concentration dependent.

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As you can see from the graph, the line is in two stages – the first part representing zero order is a straight line but the second part where first order kinetics is demonstrated gives an exponential decay curve.

First order kinetics •

Most drugs are eliminated with first order kinetics.

•

The T0.5 is constant

•

Rate of removal depends on how much drug is present

A constant fraction is removed in unit time

•

The normal plot is usually transformed by plotting plasma concentration as the logarithm of

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plasma concentration against time (log Cp vs t) •

From the graph it is possible to calculate T0.5, original concentration of drug in plasma, the volume of distribution of the drug and its clearance.

However it is inconvenient to try to perform calculations from these sorts of plots so we transform the line to make life a little easier for ourselves. We achieve this plotting time against the logarithm of plasma concentration or by plotting on semi-logarithmic graph paper. We will only use the semilogarithmic graph paper approach in the workshop.

This is the appearance of a semi-logarithmic plot which is a way of presenting the data. The horizontal axis is linear whilst the vertical axis is logarithmic. As you can see it gives us a straight line so that we are able to make various calculations and predictions about the way the drug is being handled by the body.

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Individuals don’t just take one drug just the once. Often we have to take a drug several times a day. As the amount of drug in plasma may well influence its action we prefer to have a steady state concentration where dose in is balanced by elimination out. As you can see from this plot although there is a little bit of movement up and down of the line by timing the doses we are able to achieve a reasonable sort of steady state.

Pharmacokinetics - Distribution • Distribution – the transfer of drugs in and out of the various tissues of the body •

Remember that this relates to the therapeutic objective of maintaining an adequate concentration of drug at the site of action

•

As it is difficult to measure the amount at the site of action, the practice is to measure the amount in blood.

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The amount of drug present is crucial It is important to achieve the right amount of drug into the right place. The distribution of the drug is a vital part of ensuring this as if too little drug is present then no effect is achieved whereas if too much drug is present then adverse reactions and possible toxicity will occur. The amount of drug that is effective falls intro what we refer to as the therapeutic window. Drugs usually reversibly distribute into various tissues of the body, this depends upon: 1. The perfusion rate of the tissue (i.e. blood flow through the tissue) 2. The physicochemical ability of the drug to cross membranes 3. The nature of the membranes 4. The extent to which the drug is bound (note only free or unbound drug is available to diffuse across membranes) It is important to emphasise that distribution is dynamic. Drugs are always “on the move” and will enter and leave compartments. Apart from the basic physicochemical influence distribution is very much affected by blood flow through the system, obviously the greater the flow rate the more drug that will pass through the tissue – tissues that are well vascularised (= plenty of blood vessels) such as the liver…. the kidney…. will receive more of a drug than other parts of the body. Drugs may be “bound” or attached to some part of the body.

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It is useful to have some sort of overview of the main pattern of distribution. This is a useful “skeleton” to try to bear in mind. Each main compartment here can obviously be sub-divided further e.g. blood into cells and plasma. Try to remember that there is reversible movement...