Basic aspects of excretion and elimination of drugs

1. Excretion Of Drugs……
Dr. kiran G Piparva
Assistant professor, Pharmacology
department,
AIIMS, Rajkot.
1/12/21

2. Metabolic
inactivation
Excretion
Drug elimination is sum total of
CLEARANCE

3. Drug Elimination
• The onset of pharmacological response depends on:
• Drug absorption (rate of absorption)
• Drug distribution (faster distribution)
• The duration and intensity of action depends upon:
• Tissue redistribution of drug and
• The rate of elimination

4. What is drug elimination??
• Elimination : Removal of the drug and its metabolite from body.
• Excretion is defined as the process whereby the drugs and/or their
metabolites are irreversibly transferred from internal to external
environment.
Type of elimination
RENAL Non Renal: Intestinal, Biliary, Pulmonary,
Salivary, Skin

5. Renal Elimination

7. Converts non
polar (lipid
soluble)
substances
In to polar
(lipid
insoluble)
substance
No
reabsorption
in renal
tubules
Excretion
in urine

8.  Water soluble
 Smallmolecular
size (<500dalton)
 Nonvolatile
Principle of renal elimination
1. Glomerular filtration
2. Tubular secretion.
3. Tubular reabsorption.
Characteristics of drug
excreted in urine
(Rate of Filtration – Rate of Reabsorption + Rate of Secretion ) = Net Renal
excretion

9. 1. Glomerular filtration:
• All FREE drugs, NON protein bound (lipid
soluble or insoluble) are filtered
• Normal GFR is 120 ml/min
• Glomerular filtration depend upon …
• Plasma protein binding
• Renal blood flow.
Must not be
affected by
Drug

10. 2. Tubular reabsorption
• 99% of glomerular filtrate is reabsorbed
• Reabsorption depends upon- lipid solubility and ionization, urinary PH
• Nonlipid soluble = Rate of excretion parallel to G.F.R.
• Highly ionized drug E.g. aminoglycoside, antibiotics
• Urinary PH- affect reabsorption process:
a. Weak acid- ionized more at basic PH- less reabsorbed- more excreted
b. Weak base- ionized more at acidic PH- less absorbed – more excreted
WATER SOLUBLE
& HIGHLY
IONIZED drug=
GFR

11. • Modification of urinary PH (ion trapping)
• For facilitating elimination of the drugs in poisoning cases.
Urine acidification : with ammonium chloride (NH4CL) –increase elimination
of basic drugs. E.g. Morphine and amphetamine poisoning-
Urine alkalization : with sodium bicarbonate (NHCO3) –increase elimination
of acidic drugs- Aspirin and Barbiturate poisoning (practically not utilized
because induces cardiotoxicity)
Effect of urinary PH - greatest: Pka between 5-8 - significant passive
reabsorption occurs

12. 3. Active tubular secretion
• Transporters: Bidirectional
Carrier mediated,
Saturable
Unaffected by Ph
• Organic acid transport (OAT): penicillin,
probenecid, uric acid ,
salicylic acid
• Organic base/cationic transport(OCT): thiazide
cimetidine,
furosemide, quinine
• Another transporters: P-gp, MRP2

13. • When renal clearance of a drug is > G.F.R. (120ml/min) = additional tubular
secretion.
• Bilateral transportation : majority exogenous agents - secreted and
endogenous substances – reabsorbed
• Only free drugs are transported : promotes dissociation of protein
binding of drug-
• Drug interaction at transport process
• Two structurally similar drugs having similar ionic charge and employing
the same carrier- mediated process for excretion enter into competition
• E,g probenecid- OATP- block active transport of penicillin and uric acid.

14. Probenecid
inhibit OAT
inhibit
secretion of
Penicillin from
blood to urine
increase half
life of penicillin
Probenecid
inhibit OAT
inhibit
reabsorption of
Uric acid from
tubule
increase excretion
of uric acid in
urine

15. • Therapeutic advantages of competition:
• Probenecid inhibits active tubular secretion of organic acids
e.g. Penicillin, PAS, PAH,17-ketosteroids: increases their
plasma conc. 2 fold.
• Probenecid acts as a uricosuric agent in treatment of gout.
 It suppresses the carrier mediated reabsorption of
endogenous metabolite uric acid.
15

16. PHYSICOCHEMICAL
PROPERTIESofdrugs
Plasma protein
binding
Renalboldflow Kinetic of
elimination
Biological factor
Disease state
Drug-Druginteraction
UrinaryPH
20/09/17
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Factors affecting renal elimination

17. Non renal routes of drug elimination
17

18. 48
Faecal elimination :
Unabsorbed drugs and drugs
conjugated metabolites secreted through
bile are eliminated in faces.
• E.g. Streptomycin
• Neomycin
• Magnesium sulphate
• Bacitracin
• Cholestyramine
• Erythromycin

19. 20/09/17
E IONFD
• Gaseous and volatile substances
• E.g. Volatile General anaesthetics
(Halothane) : absorbed through lungs
by simple diffusion.
• Intact gaseous drugs are excreted but
not metabolites
Pulmonary route

20. 41 20/09/17
XCR IONOFDRUGS
• Salivary & Skin elimination :
• Skin: Iodine, potassium iodide, lithium, phenytoin
• Hair follicles: Arsenic, Mercury, Iodides
• Sweat: Rifampicin, Amines, urea derivatives, heavy metals

23. Part 2 ..….
Dr. kiran G Piparva
Assistant professor, Pharmacology
department,
AIIMS, Rajkot.
2/12/21

24. Part : 2
Kinetics of elimination

25. •PK parameters: Provide basis for devising rational
dosage regime and its modification according individual need.
• Parameters are………
• Bioavailability (F)
• Volume of distribution (V)
• Clearance (CL)
- Plasma half life (t1/2)
- Repeated drug administration
- Plateau principle
- Target level strategy

26. Metabolic
inactivation
Excretion
Drug elimination is sum total of
CLEARANCE

27. 1. Clearance (CL)
• Clearance: The clearance (CL) of a drug is the theoretical volume of plasma
from which drug is completely removed in unit time.
• Rate of Elimination : Amount of drug eliminated /unit time
CL = Rate of elimination (RoE) c = plasma conc
C
• Example = If a drug has Plasma conc is 20 mcg/ml and RoE is 100
mcg/min
• CL = 100/20 = 5 ml /min

28. a. First Order Kinetics (exponential)
b. Zero Order kinetics (linear)
c. Nonlinear elimination
Clearance depend upon kinetics of elimination

29. a. First Order Kinetics (exponential)
• Constant fraction (%) of drug is eliminated per unit time.
 Rate of elimination is directly proportional to drug concentration.
 Majority drugs follow first order kinetics
• 200ug/ml 100ug/ml 50ug/ml 25ug/ml
2hr 2hr 2hr
50% 50% 50%
Clearance remain constant
 Do not saturate elimination process over therapeutic concentration range

30. b. Zero Order Kinetics
• Constant amount of drug is eliminated per unit time.
 Rate of elimination remain constant irrespective of drug concentration.
 Only few drugs follow zero order kinetics: Ethylalcohol
 Also called capacity limited elimination/ Michaelis-mentos elimination.
• 200ug/ml 180ug/ml 150ug/ml 120ug/ml
2hr 2hr 2hr
30ug/ml 30ug/ml 30ug/ml
Clearance with increases in concentration

31. DRUGS SHOWING ZERO ORDER KINETICS
ZERO Zero order kinetics shown by
W Warfarin
A Alcohol & Aspirin
T Theophylline
T Tolbutamide
POWER Phenytoin
MNEMONIC :Zero WATT power

33. Zero Order: Rate of Elimination is CONSTANT
First Order :Rate of Elimination ∝ Plasma Concentration
Rate of Elimination ∝ {Plasma Concentration}Order

34. First Order Kinetics Zero Order Kinetics
Constant fraction of drug is eliminated / unit
time.
Constant amount of the drug is eliminated /unit time.
Rate of elimination ∝ Plasma concentration Rate of elimination does NOT depend plasma
concentration. Or it is constant
Constant Clearance Clearance > at low concentrations ;
Clearance < at high concentrations
Constant Half -Life Half-life decrease at low concentrations and increase high
concentrations
Followed by Most Drugs Followed by very few drugs
e.g. alcohol
Any drug at high concentration (when metabolic or
elimination pathway is saturated) may show zero order
kinetics.

35. c. Nonlinear elimination
• Elimination of some drugs approaches
saturation over the therapeutic range ,
kinetic changes from first order to zero
order at higher doses.
• As result on increasing dose- plasma
concentration increases disproportionately
• Also called “ Nonlinear elimination” as
log dose-plasma conc curve is curved.
Zero order rate at
high doses
Mixed order rate
at intermediated
doses
First order rate at low
doses
Phenytoin

36. 2. Plasma half-life (t1/2)
• Defined as time taken for plasma
concentration to be reduced to half of
its original value.

37. • Forone compartment distribution, drugs having 1st
orderelimination and givenI.V……
• Twoslopes
• Alpha- initial rapidly declining due to
distribution Beta- later lessdeclined due to
elimination
• Half-lives calculated from the terminal slopesare
(beta slope): called the half-time of thedrug
• Most drugs havemulticompartment distribution
and multiexponential decayof plasmaconcentration-
time plot.

38. Elimination t1/2 = log2 = 0.693
k k
In2 = natural logarithm of 1/2= (0.693)
k = Elimination rate constant
k = CL
Vd
CL = (fraction of total amount of drug which is removed unit time)
So t1/2 = 0.693 x Vd
CL
T½ is a useful parameter can be obtained for Vd and CL

39. Plasma half-life….
So t1/2 indicate stay of drug in body
1 half-life …………. 50%
2 half-lives………… 25%
3 half-lives …….………12.5%
4 half-lives ………… 6.25%
5 half-lives ………… …3.125%
• 1st order kinetics – t1/2 does not change (V and CL remains unchanged
• 0 order kinetics – t1/2 increases (CL decreases as dose is increased)
50 + 25 + 12.5 + 6.25 = 93.75= after 4
half life
after 5 t1/2= nearly complete drug
eliminated

40. 3. Repeated Dose administration
• Steady State: The amount of drug administered is equal to the
amount of drug eliminated within one dosing interval resulting in a
plateau or constant serum drug level.
• Drug with short half life- reaches steady state rapidly
• Drug with long half life – take days to week to reach steady state
• At steady state:
• Elimination = input

41. 3. Repeated Dose administration
• At steady state (Cpss)
Elimination = input

43. Repeated Dose administration conti…
•At steady state, elimination = input
Cpss = dose rate
CL
Dose rate (oral route) = target Cpss x CL
F
Dose Rate = target Cpss x CL
First order kinetic of elimination
Zero order kinetic of elimination

44. • When drug follows 1st order kinetic:
• Dose rate & Cpss relationship is linear .
• When drug follows zero order kinetics/ non
linear kinetics: CPpss increases
disproportionately to change in dose rate.
Rate of elimination= (Vmax)(C)
Km+C
Vmx=max rate of drug elimination
C=plasma conc.
Km= plasma conc at which elimination rate is half maximal
Ave
Cpss
Dose
Rate

45. 4. The Plateau Principle of drug accumulation
Repeated dosing:
•When constant dose of a drug is
repeated before 4 t ½ it would achieve
higher peak concentration because of
residual of previous dose. It will continue
till rate of elimination balances amount of
dose administration.
•Subsequently plasma concentration
Plateaus and fluctuates about average
Cpss. This is know as plateau principle.

47. • Amplitude of fluctuation in plasma
concertation at steady state depends
on..
- Dose interval relative to its t1/2.
• Fluctuation in amplitude of plasma
concentration must be clinically
acceptable. (because concentration
beyond or below leads to toxicity or
loss of efficacy respectively
particularly narrow therapeutic index
drugs).
What is importance of plateau principle???

49. THERPEUTIC DRUG
MONITORING
Why needed?
In which drugs not needed?

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EXCRE DR S 50
METHODSTOPROLONG
DRUGACTION

51. THEABSORPTION
THEPROTEINBINDNG
THEMETABOLISM
THEEXCRETION
Prolongationof drug action
20/09/17
EXCRE DR S 51