Pharmacokinetics:

ASMAH NASSER, M.D.

Pharmacokinetics:

What Happens After Drug Administration?

Absorption Distribution MetabolismElimination /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 VdDrugs that are highly protein bound has a

low VdVd = 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 AlbuminBasic drugs binds to α–acid glycproteinDrugs 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 (trimethoprim-cotrimoxazole- a type of sulfa drug). Shortly after, she develops easy bruising and bleeding.

What is the cause for this?

ELIMINATION

Pharmacokinetics

Elimination

Most drugs undergo First order kinetics. Rate of elimination is directly proportional to plasma

concentration of the drugFew 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/CLVd = Volume of distributionCl = 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

Organs of drug elimination

10µg/ml

500µg per min

< 10µg/ml

CL = 500µg/min10µg/ml

= 50ml/min

Drug in Plasma

……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….

……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….

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 reachedSteady 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 Dosing Stopped (h)

0.0 0.5 1.0 2.0 3.0 4.0 5.0 6.0 8.0

Plasma Concentration (mg/mL)

7.06.45.84.63.73.02.41.91.3

EXCRETION

Pharmacokinetics

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

filtration

• Filtration ……. free drug only, not protein bound• Reabsorption….passive, lipid soluble form only (pH)• Secretion ……. active, acids and bases

Reabsorption

secretionFiltration

secretion

Glomerular FiltrationAll 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 solubilityDepends on pH of urineLipid 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 drugTakes 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 urineAcidic 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. A patient has overdosed on phenobartital. Phenobarbital is an acid. How to increase Phenobarbital is an acid. How to increase renal secretion of this drug?renal secretion of this drug?

QuestionA 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