PHRM 3052 Week 1 - Clearence

7/30/2019 PHRM 3052 Week 1 - Clearence

http://slidepdf.com/reader/full/phrm-3052-week-1-clearence 1/26

PHRM 3052

Biological Fate of Drugs B

Lecture 2



Objectives of lectures 2 & 3

• Why do we need pharmacokinetics?

• What are the practical upshots of pharmacokinetics?

• What is the most importantpharmacokinetic parameter – and howdoes it affect the biological fate of drugs?



Why we needpharmacokinetics?

• 3 case scenarios are presented



Scenario 1

• Drug X is recommended to be given at a dose of 500 mgevery 6 hours (from MIMS).

• You are presented with two patients:

– Patient 1: a young fit, healthy, male, aged 20 years, weight 82kg, height 183 cm.

– Patient 2: an elderly female, aged 84 years, with multiple organpathology, weight 43 kg, height 155 cm.

• Should they get the same dose?

• If not – why not and who should get what dose?



Scenario 2

• A dentist reads that the half-life of diazepam is40 hours and for midazolam is 3 hours; yet,when he gives them IV for hypnosis his patients

remain asleep for the same length of time(approx 30 minutes).

– He doesn’t understand how this can be – canyou explain?



Scenario 3

• A general medical physician has prescribed frusemide 40mg in the morning and at midday for symptomatic relief of heart failure. The patient, however, works morningshifts as a taxi driver and finds the dosing regimen to be

inconvenient.

• The physician wants to maintain the same level of diuresis, but to give the dose as 2x40mg in the morning

• When given in this dosing schedule the patients’

symptoms are not as well controlled. – Can you explain what is happening?



What is pharmacokinetics?



Dose C Effect

pharmacokinetics pharmacodynamics

Clinical Pharmacology

C = concentration



What are the practical upshots of pharmacokinetics

• The oft quoted raison d’ être of “clinical” pharmacy is to ensure that the right patientreceives the right dose of the right drug by the

right route using the right formulation at theright time .

• Clinical pharmacokinetics is all aboutdetermining the correct dose rate (not just the

dose but also how often).



Important aspects of clinical PK

• Clinical PK is about studying the movement of drug into(absorption), within (distribution) and out of (elimination) the body (usu. systemic circulation).

• The most important aspect from a dosing viewpoint is toachieve the desirable concentration at the site of actionfor the desired period of time.

• However since the concentration of drug at the site of action is often unknown or theoretical it is usual tomeasure the plasma (or blood or serum) concentrationof drug as a surrogate of this effect-site concentration.



Blood, plasma or serum???

What’s what? Are they interchangeable?

Does it matter which we use?



The passage of drug around the body

• Most drug movement processes are due topassive diffusion, therefore the driving factor isconcentration.

• This means that the higher the concentrationthe greater the amount that crosses themembrane – until equilibrium is reached.

• This concentration-dependent process is termedfirst-order (most drugs).

• If the movement was active, i.e. independent of concentration, then it would be said to be zero-

order.



What does a first-order process look like?

0

5

10

15

20

25

0 2 4 6 8 10 12

time (hours)

The higher theamount in thebody the faster

the rate of elimination(slope)

Slower rate of

elimination (slope)when amount inbody is lower

A m o u n t



What does a zero-order process look like?

0

5

10

15

20

25

0 2 4 6 8 10 12

time (hours)

The rate of elimination isindependent of theamount in the body

A m o u n t



How do we describe the clinical PK process?

In the simplest modelwe describe the body

as a box(compartment) intowhich all drug isadministered and

from which drug iseliminated

input

output



The simple one compartment view of the body

• In the previousrepresentation the sites thata drug can distribute to aregrouped together

• This means that we assumethat equal amounts of drugdistribute to every part of thebody including: arms, legs,lung, heart, spleen, bladder,

big toe etc• Although wrong, this simple

model often works quite wellwhen interpreting plasmadrug concentrations.

skeletal muscle, GIT,epidermis, CNS, CVS,visceral tissue,extracellular fluid,liver, kidneys, lungs,

bone …

Clearance



0

5

10

15

20

25

0 2 4 6 8 10 12

time (hours)

Rate of Elimination (RE)

• If the elimination rateof a drug is dependenton the amount (conc)

and is alwayschanging – how canwe describe the body'sability to get rid of the

drug?

Elimination rate= tangent of curve (mg/h)

A m o u n t



Rate of eliminationvs.

elimination rate constant

Rate of elimination

elimination rate constant

• The elimination rate constant is a

constant!• The rate of elimination is almost never

constant!



Rate of elimination vs. elimination rate constant

• The rate of elimination [RE] (mg/h) is a variablethat, for drugs that display first-order PK,constantly changes over time

• The elimination rate constant [k e ] (/h) is aconstant that describes the relationship betweenthe amount of drug in the body [ Ab ] and therate of elimination for drugs that display a first-order process,

ie RE = Ab x k e



• So we really need something that

– Is constant

– Does not rely on us knowing the amount of

drug in the body

– Will help describe the plasma concentrationafter a dose of drug…



Clearance (CL)

• Clearance is a constant that describes therelationship between the plasma drug concentration(C) and rate of elimination (RE).

• RE = CL x C• C has units of mass/volume (eg mg/L)

• RE has units of mass/time (eg mg/h)

• CL is the ratio of RE to C ie

h L L

h

Lmg

hmg

Lmg

hmg CL /

/1

/1

/

/

/

/



1st definition of CL

A constant relating the rate of elimination to the plasma concentration

RE = CL x C

• What does this mean?

• Why do we need to know this?



What does this mean - an analogy

Dose rate

(mg/h) =waterfrom tap

Plasmaconcentration(mg/L) =

volume of water in bath

Rate of elimination

(mg/h) =waterdrainingfrom bath

Clearance(L/h) =size of

plug hole



Clearance is the plug hole of parameters

• The driving force for drug elimination is theconcentration in the plasma.

• The rate that water can drain from the bath at

any time is the product of the volume of waterand the size of the plug hole:

Rate of elimination from bath

= volume x plug hole sizein PK terms RE = C x CL



At steady state

the rate of water from the tap

= the rate of water draining

hence RE = MD (maintenance dose rate)

Therefore:

MD (mg/h) = CL (L/h) x Css,ave (mg/L)



CL is the most important PK parameter

• For any drug dosed to steady state the only PK parameter that describes the relationship between doserate and average plasma concentration is clearance.

• Since most drugs are dosed on multiple occasions (ie tosteady state) then CL is the most important PK parameter.

• But CL has strange units: volume per time (L/h) – howcan this be interpreted clinically?

Documents

PHRM 3052 Week 1 - Clearence