Download 5. Pharmacokinetics3 Distrubution and Elimination

Pharmacokinetics:
ASMAH NASSER, M.D.
What Happens After Drug Administration?
 Absorption
 Distribution
 Metabolism
 Elimination /Excretion
Volume of Distribution
The measure of the space available in the body to
contain the drug.
Drugs that attaches to tissues has a high Vd
Drugs that are highly protein bound has a low Vd
Vd = Amount of drug concentration in the body
Plasma drug concentration level
Plasma Protein Binding of drugs
 Drugs attaches to PP and stay in an inactive form.
They serve as reservoirs and unbound to maintain
equilibrium.
 Acidic drugs binds to Albumin
 Basic drugs binds to α–acid glycprotein
 Drugs that are highly PPB (>70%): Sulfas,
Phenytoin, Warfarin
Question
 68 year old woman with PMH of recurrent DVTs
placed on lifelong Warfarin developed a urinary tract
infection. She was placed on Bactrim (trimethoprimcotrimoxazole- a type of sulfa drug). Shortly after,
she develops easy bruising and bleeding.
 What is the cause for this?
Pharmacokinetics
ELIMINATION
Elimination
 Most drugs undergo First order kinetics.
 Rate of elimination is directly proportional to plasma
concentration of the drug
 Few drugs undergo Zero order kinetics
 Rate of elimination is independent of plasma concentration of
the drug
 i.e. Alcohol
First order kinetics
 Rate of elimination is related to the plasma
concentration. A certain portion of the concentration
of the drug is eliminated throughout a period of time.
 A constant fraction (instead of amount) of a drug
is being eliminated per unit time
•
Example : 64 mg, 32 mg, 16 mg, 8 mg, 4 mg, 2 mg, 1 mg,
0.5 mg, 0.25 mg, 0.125 mg, 0.0625 mg, etc.
Plasma half life (T ½)
 Also known as the Elimination half life.
 Time required to reduce the plasma concentration of
a drug dose to half.
 A half life is a constant that follows first order
kinetics.
Purpose of Plasma half life (T ½)
 Useful in estimating:

The duration of action of a single dose

time to reach steady state concentration.. (Css) of drug
(chronic dosing),Usually 4-5 T1/2

Ultimately decides the dosing interval
Plasma Concentration time plot of a drug eliminated by first
order kinetics after a I.V. Injection
 1 t1/2 =50% drug
eliminated
 2 t1/2 =75% drug
eliminated
 3 t1/2 =87.5%
drug eliminated

 4 t1/2 =93.75%
drug eliminated
Half life (T ½)
 t1/2 =0.7xVd/CL
 Vd = Volume of distribution
 Cl = clearance
 OR
 k = 0.693/T1/2
 t1/2 =0.693/k
Elimination
The pharmacokinetic parameter which gives a
quantitative measure of drug elimination is
named…..
Clearance
Definition of Clearance
 The Clearance (Cl) of a drug is defined as the
volume of a biological fluid (generally plasma)
from which that drug is removed ("cleared") in the
unit of time (min).
 Stated in another way, Clearance is the rate of
elimination of a drug by all routes, relative to the
concentration of that drug in any biological fluid.
Clearance
 Clearance of a drug is the factor that predicts the rate
of elimination in relation to the drug concentration
 CL = Rate of elimination
plasma conc
 expressed as ml/minute
It is the volume of the plasma (blood)
cleared of the drug in unit time
OR
CL=VdxKd
Why is clearance important?
 Clearance determines:
 Maintenance dose
 Loading dose
 Peak onset of action
 Duration of action of drug
Drug in Plasma
…………………
…………………
…………………
…………………
…………………
10µg/ml
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
.
Organs of drug
elimination
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
…………………
<. 10µg/ml
CL = 500µg/min
10µg/ml
500µg per
min
= 50ml/min
Steady state concentration… Css
 On continuous steady administration of a drug, plasma
concentration will rise fast at first, then more slowly and reach a
plateau, where
rate of administration = rate of elimination
i.e steady state is reached
 Steady state (Css) is the situation at which the rate of drug
administration is equal to the rate of drug elimination so that
the amount of drug remains constant
Steady state concentration… Css
 On continuous steady administration of a drug, plasma
concentration will rise fast at first, then more slowly and reach a
plateau, where
rate of administration = rate of elimination
i.e steady state is reached
 Steady state (Css) is the situation at which the rate of drug
administration is equal to the rate of drug elimination so that the
amount of drug remains constant
Loading dose
 Repeated dosing or one large dose/bolus to initiate a
target plasma drug level rapidly.
 Clearance determines the drug concentration at
steady state during continuous administration
 Because elimination is occurring to some extent all
the time, if we just administer the maintenance dose,
it will take some time to reach steady state
 Therefore, we can give a loading dose to “fill up” the
system, so that steady state is achieved more quickly
Loading dose
 Loading dose = Vd x Target Concentration
bioavailability
(rememeber!) Vd = Amt of drug in
body/Plasma drug concentration
Maintainance Dose
 In most clinical situations, drugs are administered in such a
way as to maintain a steady state of drug in the body, ie, just
enough drug is given in each dose to replace the drug
eliminated since the preceding dose. Thus, calculation of the
appropriate maintenance dose is a primary goal.
Maintainance dose =
clearance x plasma conc
bioavailability
What is the half life?
 Time After Aminoglycoside  Plasma Concentration
Dosing Stopped (h) (mg/mL)
7.0
0.0
6.4
0.5
5.8
1.0
4.6
2.0
3.7
3.0
3.0
4.0
2.4
5.0
1.9
6.0
1.3
8.0
Pharmacokinetics
EXCRETION
Drug Elimination
 Drugs are eliminated from the body by two different
processes:
1) Biotransformation (the biotransformed drug is
no longer present as such in the body)
2) Excretion (the drug is transported outside the
body via the kidney and other organs)
Renal Excretion
Depends on following factors
 Glomerular Filtration
 Tubular reabsorption
 Tubular secretion
Reabsorption
filtration
secretion
secretion
Filtration
• Filtration ……. free drug only, not protein bound
• Reabsorption….passive, lipid soluble form only (pH)
• Secretion ……. active, acids and bases
Glomerular Filtration
 All protein unbound drug is filtered
 Doesn’t depend upon lipid solubility of the drug
 Depends on protein binding and renal blood
flow
Tubular reabsorption
Depends on ionization and lipid solubility
 Depends on pH of urine
 Lipid soluble drugs are reabsorbed back
 Ionized drugs cannot be reabsorbed
 (Think of the same concept we’ve spoken back in
the Absorption lecture)
REMEMBER!
 Acidic drugs are better Absorbed in Acidic medium
(low pH) ….AAA…

eg: Aspirin better absorbed in stomach
 Basic drugs Better absorbed in Basic medium (high
pH)……BBB

Eg: Amphetamine better absorbed in Intestine
 Absorption is better if drug is non-ionized
(Uncharged, lipid soluble, unpolarised) because it can
cross the cell membrane
 Excretion is better if the drug is more ionized
(Charged, Lipid insoluble , Polarised , Water soluble)
because it cannot cross the cell membrane
Tubular secretion
 Independent of plasma protein binding of drug
 Independent of lipid solubility of the drug
 Takes place mainly at proximal convoluted tubule
by carrier mediated transport processes .Transport
systems are bidirectional.
 Competitve
Question
 Probenecid is moved into the urine by the same
transport pump that moves many antibiotics. Why is
probenecid sometimes given as an adjunct to antibiotic
therapy?
Examples of drugs that are activeily secreted
 Penicillins
 Cephalosporins
 Salicylic acid
 Probenecid
 Ethacrinic acid
Probenecid and Penicillin
 Probenecid decreases the active secretion of
penicillin, therefore inreasing the duration of action
of penicillin
Similarly…..
 Probenecid, also competes with Uric acid for
reabsorption in renal tubule. So uric acid
reabsorption is reduced and more has to be excreted
in urine…..
 Probenecid is therefore used as a treatment for?
pH of urine
 Acidic drugs are more ionized and not reabsorbed in
alkaline urine
 Basic drugs are more ionized and not reabsorbed in
acidic urine
 Acidification and alkalinization of urine will
facilitate the renal excretion of basic and acidic
drugs respectively
Alkalinize urine in Barbiturate and Aspirin poiseninig.
Acidify urine in Morphine,Amphetamine poisoning
How to treat Drug poisening by renal secretion
 Acidification of urine (in basic drug poisoning)

Give Ammonium chloride

i.e. Morphine, Amphetamine overdose
 Alkalinization of urine(in acidic drug poisoning)

Give Sodium bicarbonate

i.e. Aspirinoverdose
Summary of Excretion
 Acidification of urine (in basic drug poisoning)


Give Ammonium chloride or Vitamin C or Canberry juice
Urine acidified in Morphine, Amphetamine poisoning
 Alkalinization of urine(in acidic drug poisoning)

Give Sodium bicarbonate or Acetazolamide

Urine alkalinized in Barbiturate,Aspirin
 Probenecid is combined with penicillin to increase penicillin's
duration of action
 Probencid is used in Gout!!!! Promotes excretion of uric acid
Question
 A patient has overdosed on phenobartital.
Phenobarbital is an acid. How to increase renal
secretion of this drug?
Question
 A patient who experiences migraines has accidentally





overdosed with methysergide, a weak base of
pKa=6.5. If urinary pH in this patient is 5.5, which of
the following statements regarding elimination of
methysergide from the body is accurate?
A. Increase in urinary pH will increase excretion
rate.
B. Urinary excretion is already maximal, and changes
in pH will have no effect.
C. Attempts should be made to acidify the urine to at
least 4 units below drug pKa.
D. At urinary pH of 5.5, methysergide is 99% ionized.
E. None of the above