ASMAH NASSER, M.D. Pharmacokinetics:
Jan 11, 2016
ASMAH NASSER, M.D.
Pharmacokinetics:
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 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 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/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 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 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 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 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 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. 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?
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