Elimination of Drugs

1. Dr.Muhammad Usman Khalid
DRUG ELIMINATION

2. DRUG ELIMINATION
The irreversible loss of drug from the body
Metabolism
Excretion

3. KINETICS OF METABOLISM / ELIMINATION
First order kinetics
Zero-order kinetics

4. FIRST ORDER ELIMINATION
 There is elimination / metabolism of a
constant fraction of drug per unit time.
 The rate of elimination is directly proportional
to drug concentration
 Elimination systems are not saturated by
drugs
 Most drugs are eliminated by first order
(exponential) kinetics

6. ZERO-ORDER KINETICS
Nonlinear , Capacity limited
elimination, saturation kinetics,
dose- or concentration
dependent, &
Michaelis-Menten elimination
Rate of elimination = VmaxX C
Km + C

7. ZERO-ORDER KINETICS
 A constant amount of drug will be
eliminated per unit time (e.g., 10 mg will
be eliminated every 8 hours)
 The amount of elimination remains
constant over time irrespective of drug
concentration
 Eliminating mechanisms are saturated

8. DRUGS ELIMINATED BY ZERO-ORDER KINETICS
Aspirin
Ethanol and
Phenytoin

10. KINETIC CHANGES FROM FIRST TO ZERO ORDER
 When therapeutic doses of drugs exceeds
the capacity of elimination mechanisms
 As a result plasma concentration ↑es
disproportionately with ↑ in dose – at high
therapeutic or toxic concentration
Aspirin, phenytoin, tolbutamide,
theophylline, warferin
Over most of its plasma
concentration range -- ethanol

12. • Constant fraction Constant am
• Elimination systems
are not saturated are saturated

13. DRUG ELIMINATION
The irreversible loss of drug
from the body
Metabolism (biotransformation)
Excretion --- Removal of
chemically unchanged drug
or its metabolite from the
body.

14. HOW BIOTRANSFORMATION HELPS IN
EXCRETION OF DRUGS?
Biotransformation involves two kind
of reaction, phase I and phase II.
Both phases ↓ lipid
solubility
Drugs become more hydrophilic
-------Increase renal / bile
excretion

15. THE MAIN ROUTES OF ELIMINATION/EXCRETION
The kidneys
The hepatobiliary
system
The lungs (volatile /
gaseous anaesthetics,
alcohol)

16. OTHER ROUTES OF ELIMINATION/EXCRETION
 Faeces – unabsorbed drug + drug secreted
in bile
 Saliva --- a unique taste of some drugs –
metronidazole, phenytoin
 Sweat --- iodide, rifampicin, heavy metals
 Tears
 Milk – with possible transfer to neonates
 Salicylates, theophylline,primidone,
ethosuximide, phenoparbitone, phenothiazines,
β-blockers

17. RENAL ELIMINATION OF DRUGS & DRUG
METABOLITES
 Three fundamental processes account for
renal drug excretion
Glomerular filtration
Active tubular secretion
Passive diffusion across
tubular epithelium

18. GLOMERULAR FILTRATION
 Only free drugs, diffuse into glomerular
filtrate
 Most drugs with the exception of
macromolecules such as heparin diffuse into
glomerular filtrate
 Lipid solubility and pH do not influence
the passage of drug into the glomerular
filtrate
 Rate of filtration depends on GFR,
concentration of free drug and its molecular
weight

19. ONLY FREE DRUGS, DIFFUSE INTO GLOMERULAR
FILTRATE
 The equilibrium between the free and
bound drug is not disturbed.
 There is no tendency of a drug to dissociate
as the blood traverses the glomerulus
 Warfarin – 98 % bound to albumin. Its
concentration in the filtrate is only 2 % of the
that of plasma

20. ACTIVE TUBULAR SECRETION IN PROXIMAL
TUBULES
 Drug molecules are transferred to the tubular
lumen by two independent and relatively
non selective carrier system
Transport acidic drugs
(endogenous -- uric acid) --
Penicillin, salicylic acid, probenecid,
Frusemide
Organic bases – Amphetamine,
Histamine

21. ACTIVE TUBULAR SECRETION
 The transportation is against an
electrochemical gradient, and Can reduce the
plasma concentration nearly to zero
 The carrier transports drug molecules
unaccompanied by water
 The free plasma concentration falls, causing
dissociation of bound drug from plasma albumin
 100% of drug, bound and free is available to the
carrier

22. ACTIVE TUBULAR SECRETION
 Penicillin –
 80% bound to plasma protein
 Cleared slowly by filtration
 Completely removed by tubular secretion
 Many drugs compete for the same transport
system leading to drug interactions
 Probenecid – prolongs the action of
penicillin by retarding its tubular secretion

23. PASSIVE DISTAL TUBULAR REABSORPTION
 Water is reabsorbed as fluid traverses the
tubule. The intraluminal concentration of drug
↑es & exceeds that of the perivascular space
 There is passive reabsorption of lipid
soluble, unionized drug
 Rate of absorption depends on
 Lipid solubility and pK of the drug
 Concentration gradient of the drug between the
urine and plasma

24. “ION TRAPPING”
 Ionized, lipid insoluble drugs cannot
diffuse back out of tubular lumen &
are excreted in the urine
 Alteration of urinary pH affect the
elimination of weak acids and bases by
affecting the degree of ionization
 Acidification of the urine will result in a higher
proportion of the un-ionized form of an acidic
drug and will facilitate reabsorption

25. PH CHANGE AND IONIZATION
 If pH drops from the pKa value by one unit
an acid becomes 91% unionized and a base
becomes 91% ionized
 If pH drops from pKa value by 2 units an
acid becomes 99% unionized and a base
becomes 99% ionized
 The acid aspirin (pKa 3.5) is 99% unionized
at pH 1.5 (gastric lumen) and 99% ionized at
pH 5.5 (urine)
 The base pethidine pKa is 99% ionized at pH 6.6
(urine)

26. DRUGS EXCRETED UNCHANGED IN THE URINE
 Percentage Drug excreted
 100-75 Frusemide, Gentamicin,
Methotrexate, Atenolol,
Digoxin
 75-50 Benzylpenicillin,
Cimetidine, Neostigmine
Oxytetracycline,
 ~ 50 Propentheline,
Tubocurarine

27. FACTOR INFLUENCE RENAL CLEARANCE
 Age --- some mechanism of renal excretion may
not be developed at the time of birth
Renal failure --- the clearance of
drug may be reduced
significantly, resulting in higher
plasma level
For those drugs with a narrow
therapeutic index, dose
adjustment may be required

29. Role of drug metabolism
Phase I and phase II reactions
↑ drug polarity
Ion trapping:
Ionized, lipid insoluble drugs
Cannot diffuse back out of tubular lumen
& are excreted in the urine

30. CLEARANCE
 The clearance of a drug is the volume of
plasma from which the drug is completely
removed in unit time
 CL = Rate of elimination / Cp
 CLr = Cu x Vu
Cp
 CLr varies for different drugs ---- from < 1ml/min
to 700 ml/min (=renal plasma flow)
 Unit of clearance is volume/time

31. • A fraction of the drug molecules present in the plasma are re
• It requires 50 ml of plasma to account for the amount of drug
eliminated every minute

32. FLOW DEPENDENT CLEARANCE
 Flow limited clearance --- Drugs with “high”
clearance
 A drug that is very effectively extracted by an organ, The blood
is completely cleared of the drug as it passes through the organ
 Change in blood flow effect the clearance more than
the disease of the organ
 Drugs with “low” clearance are removed slowly
 Specific organ clearance is the capacity of an
individual organ to eliminate the drug
 Due to metabolism – hepatic clearance
 Due to excretion – renal clearance by elimination in
urine

33. TOTAL BODY CLEARANCE
 It is the sum of the clearances from the
various drug metabolizing & drug eliminating
organs
 Cltotal = CLrenal + CLHepatic + CLPulmonary +
Clothers
 A patient in renal failure may some times
benefit from a drug that is excreted by
liver
 Total clearance can be derived from the
steady state equation

34. BILIARY EXCRETION & ENTEROHEPATIC
CIRCULATION
 By p-glycoproteins liver cells transfer drugs
from plasma to bile
 Enterohepatic circulation --- Prolongs drug
action
 Rifampicin, indomethacin, estradiol, Morphine
 Chloramphenicol, tetracycline, oral contraceptives
and erythromycin
 Drugs excreted in bile
 Vencuronium is excreted unchanged in bile
 Rifampicin is absorbed from the gut and slowly
deacylated, retaining its biological activity. Both forms are
excreted in the bile, but the deacylated form is not
reabsorbed. So eventually most of the drug leaves the
body in this form in the faeces

35. • Metabolism
• Excretion into the bile
By p-glycoproteins liver cells transfer drug molecules
from plasma to bile

37. EXTRACTION RATIO AND EXTRACTION RATE
 Extraction ratio is the decline of drug concentration
in the plasma from arterial to the venous side of the
kidney = C2/C1
 It represents the ability of an organ to remove a drug
from the perfusing blood during its passage through
the organ, and is expressed as a percentage or
fraction.
 ER = CLliver
Q
 Excretion rate
 Excretion rate = (clearance) (plasma concentration)
mg/min ml/minmg/ml

38. HALF LIFE OF A DRUG (T1/2)
The plasma half life of a drug
is the time taken for its
plasma concentration to be
reduced to half of its
original value (in the
therapeutic range) during
elimination

39. HALF LIFE OF A DRUG (T1/2)
 For drugs eliminated by first-order
kinetics
 t1/2 of a drug does not depend on the size
of administered dose
t1/2 = 0.7 Vd / CL
[The natural logrithium of 2 = 0.693 (approx ---
0.7)]

43. DOSE ADJUSTMENT AND T ½ OF A DRUG
 Adjustment of dose is required if t 1/2 of a
drug is increased by
 ↓ renal plasma flow or hepatic blood flow
 Cardiogenic shock, heart failure, or hemorrhage
 ↓ extraction ratio
 Renal diseases
 ↓ metabolism
 Another drug inhibits its biotransformation or
cirrhosis of liver

44. Nearly complete drug
elimination occurs in 4-5 half-
lives
 t1/2 --- 50% drug is eliminated
 t1/2 --- 75% (50+25)drug is eliminated
 t1/2 --- 87.5 % (50+25+12.5) drug is
eliminated
 t1/2 --- 93.75% (50+25+12.5+6.25) drug is
eliminated

46. DRUG ACCUMULATION
 Administered much faster than elimination
 If the dosing interval is shorter than 4 half-
lives, the drug will accumulate in the body
and reach toxic levels.
 Accumulation factor =
1 / fraction lost in one dosing interval
= 1 / 1- fraction remaining

47. ELIMINATION FASTER THAN ADMINISTRATION
If elimination greatly exceeds
the rate of delivery, the
concentration in the body may
never reach therapeutic
levels.

48. THANK YOU