asmah nasser, m.d. pharmacokinetics:. what happens after drug administration? absorption...
TRANSCRIPT
![Page 1: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/1.jpg)
ASMAH NASSER, M.D.
Pharmacokinetics:
![Page 2: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/2.jpg)
What Happens After Drug Administration?
Absorption
Distribution
Metabolism
Elimination /Excretion
![Page 3: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/3.jpg)
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
![Page 4: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/4.jpg)
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
![Page 5: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/5.jpg)
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?
![Page 6: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/6.jpg)
ELIMINATION
Pharmacokinetics
![Page 7: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/7.jpg)
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
![Page 8: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/8.jpg)
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.
![Page 9: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/9.jpg)
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.
![Page 10: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/10.jpg)
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
![Page 11: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/11.jpg)
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
![Page 12: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/12.jpg)
Half life (T ½)
t1/2 =0.7xVd/CLVd = Volume of distributionCl = clearance
OR
k = 0.693/T1/2
t1/2 =0.693/k
![Page 13: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/13.jpg)
Elimination
The pharmacokinetic parameter which gives a quantitative measure of drug elimination is
named…..
Clearance
![Page 14: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/14.jpg)
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.
![Page 15: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/15.jpg)
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
![Page 16: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/16.jpg)
Why is clearance important?
Clearance determines: Maintenance dose Loading dose Peak onset of action Duration of action of drug
![Page 17: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/17.jpg)
Organs of drug elimination
10µg/ml
500µg per min
< 10µg/ml
CL = 500µg/min10µg/ml
= 50ml/min
Drug in Plasma
……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….
……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….
![Page 18: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/18.jpg)
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
![Page 19: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/19.jpg)
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
![Page 20: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/20.jpg)
![Page 21: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/21.jpg)
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
![Page 22: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/22.jpg)
Loading dose
Loading dose = Vd x Target Concentration
bioavailability(rememeber!) Vd = Amt of drug in
body/Plasma drug concentration
![Page 23: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/23.jpg)
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
![Page 24: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/24.jpg)
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
![Page 25: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/25.jpg)
EXCRETION
Pharmacokinetics
![Page 26: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/26.jpg)
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)
![Page 27: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/27.jpg)
Renal Excretion
Depends on following factors
Glomerular Filtration
Tubular reabsorption
Tubular secretion
![Page 28: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/28.jpg)
filtration
• Filtration ……. free drug only, not protein bound• Reabsorption….passive, lipid soluble form only (pH)• Secretion ……. active, acids and bases
Reabsorption
secretionFiltration
secretion
![Page 29: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/29.jpg)
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
![Page 30: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/30.jpg)
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)
![Page 31: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/31.jpg)
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
![Page 32: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/32.jpg)
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
![Page 33: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/33.jpg)
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?
![Page 34: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/34.jpg)
Examples of drugs that are activeily secreted
Penicillins Cephalosporins Salicylic acid Probenecid Ethacrinic acid
![Page 35: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/35.jpg)
Probenecid and Penicillin
Probenecid decreases the active secretion of penicillin, therefore inreasing the duration of action of penicillin
![Page 36: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/36.jpg)
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?
![Page 37: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/37.jpg)
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
![Page 38: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/38.jpg)
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
![Page 39: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/39.jpg)
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
![Page 40: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/40.jpg)
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?
![Page 41: ASMAH NASSER, M.D. Pharmacokinetics:. What Happens After Drug Administration? Absorption Distribution Metabolism Elimination /Excretion](https://reader030.vdocuments.us/reader030/viewer/2022033101/56649e445503460f94b389fe/html5/thumbnails/41.jpg)
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